Spiroquinoxaline derivatives as inhibitors of non-apoptotic regulated cell-death

ABSTRACT

The present invention relates to compounds which are inhibitors of non-apoptotic regulated cell death, and to pharmaceutical compositions containing such compounds. Furthermore, the present invention relates to the use of such compounds and pharmaceutical compositions in therapy, in particular in the treatment of a condition, disorder or disease that is characterized by non-apoptotic regulated cell-death or where non-apoptotic regulated cell-death is likely to play or plays a substantial role. The compounds and pharmaceutical compositions described herein are also useful in the treatment of a condition, disorder or disease that is characterized by oxidative stress or where oxidative stress is likely to play or plays a substantial role; and/or a condition, disorder or disease that is characterized by activation of (1) one or more components of the necrosome; (2) death domain receptors; and/or (3) Toll-like receptors; and/or (4) players in ferroptotic/ferroptosis signalling, or where activation of any one of (1) to (3) and/or (4) is likely to play or plays a substantial role.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/904,377, filed Jan. 11, 2016, now issued as U.S. Pat. No.9,802,956, which application is a U.S. national phase application ofInternational PCT Patent Application No. PCT/EP2014/065145, filed onJul. 15, 2014, which claims priority to European Patent Application Nos.13176582.8, 13176581.0, and 13176580.2, all three of which were filedMay 10, 2013. These applications are incorporated herein by reference intheir entireties.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds which are inhibitors ofnon-apoptotic regulated cell death, and to pharmaceutical compositionscontaining such compounds. Furthermore, the present invention relates tothe use of such compounds and pharmaceutical compositions in therapy, inparticular in the treatment of a condition, disorder or disease that ischaracterised by non-apoptotic regulated cell-death or wherenon-apoptotic regulated cell-death is likely to play or plays asubstantial role. The compounds and pharmaceutical compositionsdescribed herein are also useful in the treatment of a condition,disorder or disease that is characterised by oxidative stress or whereoxidative stress is likely to play or plays a substantial role; and/or acondition, disorder or disease that is characterised by activation of(1) one or more components of the necrosome; (2) death domain receptors;and/or (3) Toll-like receptors; and/or (4) players inferroptotic/ferroptosis signalling, or where activation of any one of(1) to (3) and/or (4) is likely to play or plays a substantial role.

BACKGROUND OF THE INVENTION

The incidence of many debilitating conditions, disorders and diseases,especially Alzheimer's disease, Parkinson's disease, cardiac infarction,amyotrophic lateral sclerosis (ALS), organ transplantations, and stroke,is continuously increasing in ageing societies, and thus represents notonly a major health problem but also a growing socio-economic burden.Yet, and in particular, treatment strategies to combat these diseasesare inadequate or fail to exist entirely. One major underlying factor ofmany such conditions, disorders and diseases is the role ofnon-apoptotic regulated cell death, and the associated diversity ofaberrant cellular processes, which ultimately lead to cellular demise.

Cell death has been traditionally classified as apoptosis or necrosis.While apoptosis is now known and used as a term to describe a small setof lethal signalling pathways, the mechanisms for which have beenextensively studied, necrosis was, until relatively recently, consideredan unregulated process of mere accidental cell death. Little effort hadbeen made to study necrosis due to its believed unregulated nature. Morerecently, support for forms of regulated cell-death mechanism other thanapoptosis have since been found, described and standardised nomenclaturerecommended (Galluzzi et al. (2012); Cell Death Diff. 19:107-20,especially Table 1 thereof), including those termed “regulated necrosis”and “necroptosis”; a specific regulated cellular necrosis mechanisms,discrete from apoptosis as described by Hitomi et al. (Cell 135:1311-23(2008)) and Degterev and co-workers (Nat. Chem. Biol. 1:112-9 (2005)).Other forms of regulated cell death are described in Galluzzi et al.(2012), including certain tentative new names for very specificsignalling pathways that lead to cell death such as “parthanatos”,“paraptosis” and several others (see references in Galluzzi et al.2012). Another form of non-apoptotic regulated cell death includes“ferroptosis”, a non-apoptotic, iron-dependent, oxidative form ofcell-death recently described by Dixon and co-workers (Cell 149:1060-72(2012)). While necroptosis and ferroptosis share many features,differences between their phenotypes can be observed, and it is to beexpected that additional regulated cell death modalities and lethalsignalling pathways exist and may be described and defined separately tonecroptosis etc.

However, evidence is mounting that oxidative stress, a state associatedwith a high level of reactive oxygen species (ROS), is a commondenominator of many such non-apoptotic regulated cell-death processes(and also a specific form of apoptosis known as “caspase-independentapoptosis”, a pathway of regulated cell-death that operates in parallelto caspase-dependent apoptosis in response to multiple intracellularstress conditions), and in particular most neuronal dysfunction,ultimately resulting in neurodegeneration (Lin, M. T. & Beal, M. F.,Nature 443, 787-795 (2006)). Oxidative stress, the imbalance between thegeneration and clearance of ROS, is a potent inducer of cell death.Increased levels of ROS, impaired ROS regulating systems and oxidativelymodified proteins, lipids and DNA are all hallmarks of postmortem braintissues from Alzheimer's, Parkinson's and ALS patients. ROS are also amajor causative factor in the degeneration of neurons in strokepatients. Stroke is one prominent example of tissue damage caused by ROSfollowing ischemia-reperfusion injury. Tissue damage due toischemia-reperfusion injury is, however, not restricted to the centralnervous system, it is also a hallmark of infarction (cardiac infarctionbeing the most prevalent type of infarction) and an importantcomplication in surgery with special emphasis on solid organtransplantation. Oxidative stress and/or non-apoptotic regulated celldeath is associated with many other conditions, disorders and diseases,or is a symptom the result of or arising from such a condition, disorderand disease. Of particular importance is cell, tissue, organ or organismintoxication, such as circumstances which are the result of, arise fromor are associated with drug treatment (e.g., kidney toxicity fromcisplatin), drug overdose (e.g., liver toxicity from paracetamol), acutepoisoning (e.g., from alcohol, paraquat or environmental toxins) orexposure to ionizing radiation. Other conditions, disorders and diseasesresult in a state that is associated with oxidative stress and/ornon-apoptotic regulated cell death, and include head trauma, asphyxia,cold or mechanical injury and burns. Oxidative stress and/ornon-apoptotic regulated cell death may also be related to aestheticconditions such as UV-damage/aging in skin and hair loss.

Oxidative stress-dependent cell death occurs frequently in a regulatedfashion. Although there is no generalized consensus on the use of theexpression ‘necroptosis’ (Vandenabeele et al. (2010) Nat. Rev. Mol. CellBiol. 11:700-14), the terms ‘regulated necrosis’ and ‘necroptosis’ and‘ferroptosis’ (Dixon et al., Cell, 2012) are used herein and known inthe art to indicate general and specific forms (respectively) ofregulated—as opposed to accidental—necrosis (Galluzzi et al. 2012). Asindicated above, for a long time, necrosis was considered merely as anaccidental uncontrolled form of cell death, but evidence that theexecution of some forms of necrotic cell death is also finely regulatedby a set of signal transduction pathways and catabolic mechanisms isfurther accumulating (Galluzzi and Kroemer, Cell 135 26:1161-1163(2008); Kroemer et al., Cell Death Differ.; 16(1): 3-11, (2009)). Forinstance, death domain receptors (e.g., TNFR1, Fas/CD95 and TRAIL-R) andToll-like receptors (e.g., TLR3 and TLR4) have been shown to elicitnecrotic cell death, in particular in the presence of caspaseinhibitors—strong evidence of the non-apoptotic nature of regulatednecrosis and necroptosis. TNFR1-, Fas/CD95-, TRAILR- and TLR3-mediatedcell death seemingly depends on the kinase RIP1, as this has beendemonstrated by its knockout/knockdown and chemical inhibition withnecrostatin-1. While little is currently known about the molecularmechanism of ferroptosis, this form of non-apoptotic regulatedcell-death is characterised by the overwhelming, iron-dependentaccumulation of lethal lipid ROS, and in at least some cells, NOX familyenzymes make important contributions to this process, and Dixon et al.postulate that the executioners of death in certain cancer cellsundergoing ferroptosis are these ROS themselves.

Although there is no consensus on the biochemical changes that may beused to unequivocally identify oxidative stress-dependent ornon-apoptotic regulated cell-death, several mediators, organelles andcellular processes have already been implicated in such cell death(Kroemer et al., Cell Death Differ.; 16(1): 3-11, (2009)). Thesephenomena include mitochondrial alterations (e.g., uncoupling,production of reactive oxygen species, i.e., ROS, nitrosative stress bynitric oxide or similar compounds and mitochondrial membranepermeabilization, i.e., MMP, often controlled by cyclophilin D),lysosomal changes (ROS production by Fenton reactions, lysosomalmembrane permeabilization), nuclear changes (hyperactivation of PARP-1and concomitant hydrolysis of NAD+), lipid degradation (following theactivation of phospholipases, lipoxygenases and sphingomyelinases),increases in the cytosolic concentration of calcium (Ca²⁺) that resultin mitochondrial overload and activation of noncaspase proteases (e.g.,calpains and cathepsins). It is still unclear, though, how theyinterrelate with each other.

Notwithstanding, a crucial role for the RIP (receptor interactingprotein) kinases, in particular serine/threonine kinases RIP1 and RIP3,has been demonstrated for regulated necrotic cell death (Declerq et al.,Cell 138:229-232 (2009)). The multiprotein complex comprising RIP1 andRIP3 is known in the art as “necrosome”. RIP1 and RIP3 form the corecomplex within the necrosome. The necrosome complex further comprisesTRADD and FAS-associated protein with a death domain (FADD), caspase 8,the serine/threonine-protein phosphatase (PGAM5) (Micheau et al., Cell14:1814-190 (2003) and Wang et al. (2012), Cell 148:228-243) and themixed lineage kinase domain-like protein (MLKL) (Sun et al. (2012), Cell148:213-227). The necrosome regulates the decision between cell survivaland regulated necrosis. In more detail, the phosphorylation of RIP1 andRIP3 engages the effector mechanism of regulated necrosis. In contrast,if caspase 8 is activated, it cleaves RIP1 and RIP3 thereby preventingthe effector mechanism of regulated necrosis (Vandenabeele et al.,Nature Reviews Mol. Cell Biol., 11:700-714 (2010)). Accordingly, theactivation status of caspase 8 appears to be decisive whether a cellundergoes regulated necrosis or apoptosis by the initiation of thepro-apoptotic caspase activation cascade. Whether FADD or TRADD arestrictly required for the assembly of the necrosome is presently notclear.

Besides caspase 8, negative regulators of TNR-receptor-family- or Tolllike receptor-mediated regulated necrosis include E3 ubiquitin ligasescIAP1 and cIAP2, cFLIP, and TAK1, whereas the deubiquitinating enzymesCYLD and A20 act as positive regulators of regulated necrosis(Vandenlakker et al, Cell Death Differ 18, 656-665, 2011). Remarkably,the long and short isoforms of cFLIP were shown to act antagonistically,the short isoform promoting and the long isoform inhibiting TLR-ligandinduced regulated necrosis (Feoktistova et al., Mol. Cell 43, 449-463,2011). FAB2 and FAB2 are additional components of the signalling complexformed upon TNF receptor-ligation whose precise function in theregulation of regulated necrosis is still unknown. TRIF, an adapterprotein with a RIP1 homology interaction motif (RHIM) is coupling thesignalling complex formed upon Toll like receptor ligation to TLR3 andTLR4.

A RIP1 and RIP3 containing multiprotein complex promoting apoptosis orregulated necrosis is formed independently from TNF receptor familymembers in response to DNA damage-mediated depletion of cIAP1 and cIAP2.This complex further comprises FADD and caspase 8, the latter being thedecisive determinant for the choice between apoptosis and regulatednecrosis (Tenev et al., Mol. Cell 43, 432-448, 2011).

RIP1 is found in several types of complexes mediating an innate immuneresponse to RNA and DNA viruses. A complex comprising TANK, FADD, TRADD,NEMO, and RIP1 is recruited to the outer membrane of mitochondria inresponse to ligation of pattern recognition receptors RIG-I or MDA5recognizing viral RNAs through interaction with IPS1 (also called MAVS).RIP1 shares RIP1 homotypic interaction motifs (RHIM) for dimerizationnot only with RIP3, but also with the cytosolic DNA sensor DAI and TRIF(the latter being involved in signal transduction through TLR3 andTLR4). As exemplified for the murine cytomegalovirus protein M45,proteins or peptides containing a RHIM sequence may disrupt the RHIMinteraction between RIP1 and RIP3 and may thus inhibit regulatednecrosis (consensus sequence: I/V-Q-I/L/V-G-x-x-N-x-M/L/I)(Mack et al.,PNAS 105, 3094-3099, 2008; Kaiser et al., J. Immunol. 181, 6427-6434,2008). Although regulated necrosis promoting activities have not beenreported so far for the sensors of viral RNA and DNA, these RIP1containing protein complexes might nevertheless operate as molecularswitches for oxidative signals that convert a pro-survival (or aninterferon-inducing) signal into a regulated necrosis inducing signal.

In respect of ferroptosis, Dixon and co-workers (2012) cannot excludethe possibility of a death-inducing protein or protein complex that isactivated downstream of ROS accumulation as observed for that form ofnon-apoptotic regulated cell-death.

Accordingly, regulated necrosis (and potentially other related forms ofnon-apoptotic regulated cell-death such as ferroptosis) may becharacterized as a type of cell death that can be avoided byinhibiting—either directly or indirectly—the necrosome or othercomponents of ferroptotic signalling, in particular the activity and/orinteraction of components thereof such as RIP1, RIP3 and others such asone or more members of the ferroptotic pathway (either through geneticor pharmacological methods). This represents a convenient means todiscriminate between regulated necrosis (e.g., necroptosis) andaccidental forms of necrosis (Kromer et al., Cell Death Differ.; 16(1):3-11, (2009)).

Certain spiroquinoxaline derivatives, and pharmaceutical compositionsthereof, are generically disclosed in EP 0 509 398A1 and EP 0 657 166A1, in particular for use in the treatment of virus infection.

Together with a very large number of other generic structures, certainspiroquinoxaline derivatives are generically disclosed in WO 2007/117180A1 as formula 2.2, and a small number of specific spiroquinoxalinecompounds are disclosed in the expansive Table 12 thereof. WO2007/117180 A1 relates primarily to the construction and composition oflarge combinatorial libraries of small molecules having interest asmerely potential physiologically active substances and pharmaceuticalcompositions thereof. Of the huge number of specific compounds disclosedtherein, only a small number of compounds (not being spiroquinoxalines)are tested for and suggested to have anti-cancer properties (example 40and Table 14 thereof).

Frankowski and co-workers (PNAS 108:6727-32 (2012)) describe thesynthesis of a small library of Stemona alkaloid analogues (reported ashaving antitussive activity) that are fused by a spiro-carbon toquinoxaline derivatives (Scheme 4 therein), and the activity of suchalkaloid-quinoxalines spiro-fusions in various receptor-binding assays.

Various organic chemistry methods are disclosed for the synthesis ofquinoxaline derivatives and spiro forms thereof. These include, Kysil etal (Eur. J. Org. Chem. 8:1525-43 (2010)), Lee (KR 2012-105714), Adarvana(Tetrahedron Lett. 52:6108-12 (2011)), and Kolla and Lee (Tetrahedron66:8938-44 (2010)).

Other specific spiroquinoxaline compounds are known and are commerciallyavailable, but without indication of synthesis or utility. These includethose with CAS registry numbers: 1172351-24-4, 1223830-23-6 and1223982-82-8.

Accordingly, it is an object of the present invention to providealternative, improved and/or integrated means or methods that addressone or more problems, including those described above such as in thetreatment (including prophylactic treatment) of one or more conditions,disorders or diseases (or related conditions or symptoms) and/or agentsand pharmaceutical compositions useful for such treatment. Such anobject underlying the present invention is solved by the subject matteras disclosed or defined anywhere herein, for example by the subjectmatter of the attached claims.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a compound selectedfrom the group consisting of a spiroquinoxaline derivative having thegeneral formula (I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof, wherein R¹ to R⁵, ring A, E,L, and G are as specified in claim 1, for use in a method of treating(i) a condition, disorder or disease that is characterised bynon-apoptotic regulated cell-death or where non-apoptotic regulatedcell-death is likely to play or plays a substantial role; (ii) acondition, disorder or disease that is characterised by oxidative stressor where oxidative stress is likely to play or plays a substantial role;(iii) a condition, disorder or disease that is characterised byactivation of (1) one or more components of the necrosome; (2) deathdomain receptors; and/or (3) Toll-like receptors; and/or (4) players inferroptotic/ferroptosis signalling, or where activation of any one of(1) to (3) and/or (4) is likely to play or plays a substantial role;(iv) a condition, disorder or disease selected from the group consistingof a neurodegenerative disease of the central or peripheral nervoussystem, muscle wasting, muscular dystrophy, ischemia, compartmentsyndrome, gangrene, pressure sores, sepsis, degenerative arthritis,retinal necrosis, heart disease, liver, gastrointestinal or pancreaticdisease, avascular necrosis, diabetes, sickle cell disease, alterationof blood vessels, cancer-chemo/radiation therapy-induced cell-death andintoxication, or is the result of, arises from or is associated with anyof the foregoing; and/or (v) a condition, disorder or disease which isthe result of, arises from or is associated with a circumstance selectedfrom the group consisting of forms of infection of viruses, bacteria,fungi, or other microorganisms; a reduction in cell-proliferation, analteration in cell-differentiation or intracellular signalling; anundesirable inflammation; cell death of retinal neuronal cells, cardiacmuscle cells, or cells of the immune system or cell death associatedwith renal failure; neonatal respiratory distress, asphyxia,incarcerated hernia, placental infarct, iron-load complications,endometriosis, congenital disease; head trauma/traumatic brain injury,liver injury; injuries from environmental radiation; burns; coldinjuries; mechanical injuries, and decompression sickness.

In a second aspect, the present application provides a method oftreating an individual with a need thereof (in particular a humanpatient), comprising administering a pharmaceutically effective amountof (in particular a therapeutically effective dose of) a compoundselected from the group consisting of a spiroquinoxaline derivativehaving the general formula (I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof, wherein R¹ to R⁵, ring A, E,L, and G are as specified in claim 2, with the proviso that when ring Ais a monocyclic 4- to 10-membered N-heterocycloalkylene, then theindividual is not suffering from a condition, disorder or disease thatis cancer, and/or one the result of, arising from or associated withcancer.

In a third aspect, the present application provides a compound selectedfrom the group consisting of a spiroquinoxaline derivative having thegeneral formula (I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof, wherein R¹ to R⁵, ring A, E,L, and G are as specified in claim 3.

In a fourth aspect, the present application provides a compound selectedfrom the group consisting of a spiroquinoxaline derivative having thegeneral formula (I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof, wherein R¹ to R⁵, ring A, E,L, and G are as specified in claim 4 for use as medicament.

In a fifth aspect, the present invention provides a pharmaceuticalcomposition comprising a compound as specified in the first or secondaspect and a pharmaceutically acceptable excipient.

Further aspects of the invention are disclosed herein.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1: Non-inhibition of apoptotic cell-death by compounds disclosedherein. SH-SY5Y cells were propagated and seeded in 96-well plates,together with compound N-1, N-2, N-10 of Table 1-N (FIG. 1(a)), compoundO/S-6 or O/S-3 of Table 1-O/S (FIG. 1(b)), or compound C-12, C-91, orC-205 of Table 1-C (FIG. 1(c)) (each 1 μM) and TNF-alpha was added(final concentration: 10 ng/mL) to induce apoptosis. The apoptosis andpan-caspase inhibitor z-vad (final concentration: 50 μM) and thenecroptosis inhibitor Necrostatin-1 (Nec-1; final concentration: 5 μM)were used for comparison. Control wells were established with vehicleonly (DMSO), with and without treatment with TNF-alpha to induceapoptosis. Cells were incubated, and cell survival was detected andquantified. Percentage cell survival after TNF-alpha-induced apoptosisis shown (error bars indicate standard deviation (SD)).

FIG. 2: Efficacy of a compound of the invention in an animal model ofliver IRI. A significant reduction of the serum markers for liver celldamage, GPT (a) and GOT (b), compared to vehicle control, upon treatmentof mice with compound N-2 (“Cmpd”) of Table 1-N following IRI liverdamage is shown. The “Sham” bar represents the data from control animalsthat were treated to the same protocol but without atraumatic clipping.Errors shown are SEM. Significant differences are seen betweenIRI+vehicle compared to IRI+Cmpd, as well as between IRI+vehiclecompared to Sham+vehicle. No significant difference is seen betweenIRI+Cmpd and Sham+vehicle. FIG. 2(c) shows a photograph representing avisual comparison between vehicle and compound-treated livers of micefrom this study.

FIG. 3: Efficacy of a compound of the invention in an animal model ofkidney IRI. Improved survival of mice suffering kidney-ischemicreperfusion injury (IRI), compared to vehicle control, after treatmentwith compound N-2 (“Cmpd”) of Table 1-N at a dose of both 1 and 10 mg/kgwas observed.

FIG. 4: Efficiency of a compound of the invention in an animal model oftraumatic brain injury. A trend of a (non-significant) positive effectof treatment with compound N-2 (“Cmpd”), reducing the contusion volumein the brains of mice following traumatic brain injury (TBI) compared tovehicle control.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Although the present invention is further described in more detailbelow, it is to be understood that this invention is not limited to theparticular methodologies, protocols and reagents described herein asthese may vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to limit the scope of the present invention which willbe limited only by the appended claims and other disclosures herein.Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art.

In the following, the elements of the present invention will bedescribed in more detail. These elements are listed with specificembodiments, however, it should be understood that they may be combinedin any manner and in any number to create additional embodiments. Thevariously described examples and preferred embodiments should not beconstrued to limit the present invention to only the explicitlydescribed embodiments. This description should be understood to supportand encompass embodiments which combine the explicitly describedembodiments with any number of the disclosed and/or preferred elements.Furthermore, any permutations and combinations of all described elementsin this application should be considered disclosed by the description ofthe present application unless the context indicates otherwise. Forexample, if in one embodiment R⁸ of the compound of the invention ishalogen (such as Cl) and in another embodiment of the compound of theinvention ring A is 4-piperidinylene, then in a preferred embodiment, R⁸of the compound of the invention is halogen (such as Cl) and ring A is4-piperidinylene.

Preferably, the terms used herein are defined as described in “Amultilingual glossary of biotechnological terms: (IUPACRecommendations)”, H. G. W. Leuenberger, B. Nagel, and H. Kolbl, Eds.,Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

The practice of the present invention will employ, unless otherwiseindicated, conventional methods of chemistry, biochemistry, andrecombinant DNA techniques which are explained in the literature in thefield (cf., e.g., Molecular Cloning: A Laboratory Manual, 2^(nd)Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press,Cold Spring Harbor 1989).

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated member, integer or step or group of members, integers orsteps but not the exclusion of any other member, integer or step orgroup of members, integers or steps. The terms “a” and “an” and “the”and similar reference used in the context of describing the invention(especially in the context of the claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by the context. Recitation of ranges of valuesherein is merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range. Unlessotherwise indicated herein, each individual value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”),provided herein is intended merely to better illustrate the inventionand does not pose a limitation on the scope of the invention otherwiseclaimed. No language in the specification should be construed asindicating any non-claimed element essential to the practice of theinvention.

Several documents are cited throughout the text of this specification.Each of the documents cited herein (including all patents, patentapplications, scientific publications, manufacturer's specifications,instructions, etc.), whether supra or infra, are hereby incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

The term “alkyl” refers to a monoradical of a saturated straight orbranched hydrocarbon. Preferably, the alkyl group comprises from 1 to 12(such as 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbonatoms), more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl,sec-pentyl, neo-pentyl, 1,2-dimethyl-propyl, iso-amyl, n-hexyl,iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl,n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like.

The term “alkylene” refers to a diradical of a saturated straight orbranched hydrocarbon. Preferably, the alkylene comprises from 1 to 10carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, morepreferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms.Exemplary alkylene groups include methylene, ethylene (i.e.,1,1-ethylene, 1,2-ethylene), propylene (i.e., 1,1-propylene,1,2-propylene (—CH(CH₃)CH₂—), 2,2-propylene (—C(CH₃)₂—), and1,3-propylene), the butylene isomers (e.g., 1,1-butylene, 1,2-butylene,2,2-butylene, 1,3-butylene, 2,3-butylene (cis or trans or a mixturethereof), 1,4-butylene, 1,1-iso-butylene, 1,2-iso-butylene, and1,3-iso-butylene), the pentylene isomers (e.g., 1,1-pentylene,1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene,1,1-iso-pentylene, 1,1-sec-pentyl, 1,1-neo-pentyl), the hexylenisomers(e.g., 1,1-hexylene, 1,2-hexylene, 1,3-hexylene, 1,4-hexylene,1,5-hexylene, 1,6-hexylene, and 1,1-isohexylene), and the like.

The term “alkenyl” refers to a monoradical of an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond.Generally, the maximal number of carbon-carbon double bonds in thealkenyl group can be equal to the integer which is calculated bydividing the number of carbon atoms in the alkenyl group by 2 and, ifthe number of carbon atoms in the alkenyl group is uneven, rounding theresult of the division down to the next integer. For example, for analkenyl group having 9 carbon atoms, the maximum number of carbon-carbondouble bonds is 4. Preferably, the alkenyl group has 1 to 4, i.e., 1, 2,3, or 4, carbon-carbon double bonds. Preferably, the alkenyl groupcomprises from 2 to 10 carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, or 10carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbonatoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, thealkenyl group comprises from 2 to 10 carbon atoms and 1, 2, 3, 4, or 5carbon-carbon double bonds, more preferably it comprises 2 to 8 carbonatoms and 1, 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6carbon atoms and 1, 2, or 3 carbon-carbon double bonds or 2 to 4 carbonatoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon doublebond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenylgroups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl,2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl,1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl,7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl,5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, and the like. Ifan alkenyl group is attached to a nitrogen atom, the double bond cannotbe alpha to the nitrogen atom.

The term “alkenylene” refers to a diradical of an unsaturated straightor branched hydrocarbon having at least one carbon-carbon double bond.Generally, the maximal number of carbon-carbon double bonds in thealkenylene group can be equal to the integer which is calculated bydividing the number of carbon atoms in the alkenylene group by 2 and, ifthe number of carbon atoms in the alkenylene group is uneven, roundingthe result of the division down to the next integer. For example, for analkenylene group having 9 carbon atoms, the maximum number ofcarbon-carbon double bonds is 4. Preferably, the alkenylene group has 1to 4, i.e., 1, 2, 3, or 4, carbon-carbon double bonds. Preferably, thealkenylene group comprises from 2 to 10 carbon atoms, i.e., 2, 3, 4, 5,6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms,such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferredembodiment, the alkenylene group comprises from 2 to 10 carbon atoms and1, 2, 3, 4, or 5 carbon-carbon double bonds, more preferably itcomprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon doublebonds, such as 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon doublebonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. Thecarbon-carbon double bond(s) may be in cis (Z) or trans (E)configuration. Exemplary alkenylene groups include ethen-1,2-diyl,vinyliden, 1-propen-1,2-diyl, 1-propen-1,3-diyl, 1-propen-2,3-diyl,allyliden, 1-buten-1,2-diyl, 1-buten-1,3-diyl, 1-buten-1,4-diyl,1-buten-2,3-diyl, 1-buten-2,4-diyl, 1-buten-3,4-diyl, 2-buten-1,2-diyl,2-buten-1,3-diyl, 2-buten-1,4-diyl, 2-buten-2,3-diyl, 2-buten-2,4-diyl,2-buten-3,4-diyl, and the like. If an alkenylene group is attached to anitrogen atom, the double bond cannot be alpha to the nitrogen atom.

The term “alkynyl” refers to a monoradical of an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond.Generally, the maximal number of carbon-carbon triple bonds in thealkynyl group can be equal to the integer which is calculated bydividing the number of carbon atoms in the alkynyl group by 2 and, ifthe number of carbon atoms in the alkynyl group is uneven, rounding theresult of the division down to the next integer. For example, for analkynyl group having 9 carbon atoms, the maximum number of carbon-carbontriple bonds is 4. Preferably, the alkynyl group has 1 to 4, i.e., 1, 2,3, or 4, more preferably 1 or 2 carbon-carbon triple bonds. Preferably,the alkynyl group comprises from 2 to 10 carbon atoms, i.e., 2, 3, 4, 5,6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms,such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferredembodiment, the alkynyl group comprises from 2 to 10 carbon atoms and 1,2, 3, 4, or 5 (preferably 1, 2, or 3) carbon-carbon triple bonds, morepreferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4(preferably 1 or 2) carbon-carbon triple bonds, such as 2 to 6 carbonatoms and 1, 2 or 3 carbon-carbon triple bonds or 2 to 4 carbon atomsand 1 or 2 carbon-carbon triple bonds. Exemplary alkynyl groups includeethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl,4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl,4-octynyl, 5-octynyl, 6-octynyl, 7-octynyl, 1-nonylyl, 2-nonynyl,3-nonynyl, 4-nonynyl, 5-nonynyl, 6-nonynyl, 7-nonynyl, 8-nonynyl,1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl,7-decynyl, 8-decynyl, 9-decynyl, and the like. If an alkynyl group isattached to a nitrogen atom, the triple bond cannot be alpha to thenitrogen atom.

The term “alkynylene” refers to a diradical of an unsaturated straightor branched hydrocarbon having at least one carbon-carbon triple bond.Generally, the maximal number of carbon-carbon triple bonds in thealkynylene group can be equal to the integer which is calculated bydividing the number of carbon atoms in the alkynylene group by 2 and, ifthe number of carbon atoms in the alkynylene group is uneven, roundingthe result of the division down to the next integer. For example, for analkynylene group having 9 carbon atoms, the maximum number ofcarbon-carbon triple bonds is 4. Preferably, the alkynylene group has 1to 4, i.e., 1, 2, 3, or 4, more preferably 1 or 2 carbon-carbon triplebonds. Preferably, the alkynylene group comprises from 2 to 10 carbonatoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms.Thus, in a preferred embodiment, the alkynylene group comprises from 2to 10 carbon atoms and 1, 2, 3, 4, or 5 (preferably 1, 2, or 3)carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbonatoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds,such as 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplaryalkynylene groups include ethyn-1,2-diyl, 1-propyn-1,3-diyl,1-propyn-3,3-diyl, 1-butyn-1,3-diyl, 1-butyn-1,4-diyl, 1-butyn-3,4-diyl,2-butyn-1,4-diyl and the like. If an alkynylene group is attached to anitrogen atom, the triple bond cannot be alpha to the nitrogen atom.

The term “aryl” or “aromatic ring” refers to a monoradical of anaromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14(e.g., 5 to 10, such as 5, 6, or 10) carbon atoms which can be arrangedin one ring (e.g., phenyl) or two or more condensed rings (e.g.,naphthyl). Exemplary aryl groups include cyclopropenylium,cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl,anthryl, and phenanthryl. Preferably, “aryl” refers to a monocyclic ringcontaining 6 carbon atoms or an aromatic bicyclic ring system containing10 carbon atoms. Preferred examples are phenyl and naphthyl.

The term “heteroaryl” or “heteroaromatic ring” means an aryl group asdefined above in which one or more carbon atoms in the aryl group arereplaced by heteroatoms of O, S, or N. Preferably, heteroaryl refers toa five or six-membered aromatic monocyclic ring wherein 1, 2, or 3carbon atoms are replaced by the same or different heteroatoms of O, N,or S. Alternatively, it means an aromatic bicyclic or tricyclic ringsystem wherein 1, 2, 3, 4, or 5 carbon atoms are replaced with the sameor different heteroatoms of O, N, or S. Preferably, in each ring of theheteroaryl group the maximum number of 0 atoms is 1, the maximum numberof S atoms is 1, and the maximum total number of O and S atoms is 2.Exemplary heteroaryl groups include furanyl, thienyl, oxazolyl,isoxazolyl, oxadiazolyl (1,2,5- and 1,2,3-), pyrrolyl, imidazolyl,pyrazolyl, triazolyl (1,2,3- and 1,2,4-), tetrazolyl, thiazolyl,isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5-), pyridyl, pyrimidinyl,pyrazinyl, triazinyl (1,2,3-, 1,2,4-, and 1,3,5-), benzofuranyl (1- and2-), indolyl, isoindolyl, benzothienyl (1- and 2-), 1H-indazolyl,benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl(1,2,3- and 1,2,4-benzotriazinyl), pyridazinyl, phenoxazinyl,thiazolopyridinyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxathiinyl, pyrrolizinyl, indolizinyl,indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl (1,5-,1,6-, 1,7-, 1,8-, and 2,6-), cinnolinyl, pteridinyl, carbazolyl,phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (1,7-, 1,8-,1,10-, 3,8-, and 4,7-), phenazinyl, oxazolopyridinyl,isoxazolopyridinyl, pyrrolooxazolyl, and pyrrolopyrrolyl. Exemplary 5-or 6-membered heteroaryl groups include furanyl, thienyl, oxazolyl,isoxazolyl, oxadiazolyl (1,2,5- and 1,2,3-), pyrrolyl, imidazolyl,pyrazolyl, triazolyl (1,2,3- and 1,2,4-), thiazolyl, isothiazolyl,thiadiazolyl (1,2,3- and 1,2,5-), pyridyl, pyrimidinyl, pyrazinyl,triazinyl (1,2,3-, 1,2,4-, and 1,3,5-), and pyridazinyl.

The term “cycloalkyl” or “cycloaliphatic” represents cyclic non-aromaticversions of “alkyl” and “alkenyl” with preferably 3 to 14 carbon atoms,such as 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, or 10 carbonatoms, more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groupsinclude cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl,cylcodecyl, cylcodecenyl, and adamantyl. The term “cycloalkyl” is alsomeant to include bicyclic and tricyclic versions thereof. If bicyclicrings are formed it is preferred that the respective rings are connectedto each other at two adjacent carbon atoms, however, alternatively thetwo rings are connected via the same carbon atom, i.e., they form aspiro ring system or they form “bridged” ring systems. Preferredexamples of cycloalkyl include C₃-C₈-cycloalkyl, in particularcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl,bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, and bicyclo[4.2.0]octyl.

The term “cyclopropylene” means a cyclopropyl group as defined above inwhich one hydrogen atom has been removed resulting in a diradical. Thecyclopropylene may link two atoms or moieties via the same carbon atom(1,1-cyclopropylene, i.e., a geminal diradical) or via two carbon atoms(1,2-cyclopropylene).

The term “heterocyclyl” or “heterocyclic ring” means a cycloalkyl groupas defined above in which from 1, 2, 3, or 4 carbon atoms in thecycloalkyl group are replaced by heteroatoms of O, S, or N. Preferably,in each ring of the heterocyclyl group the maximum number of O atoms is1, the maximum number of S atoms is 1, and the maximum total number of Oand S atoms is 2. The term “heterocyclyl” is also meant to encompasspartially or completely hydrogenated forms (such as dihydro, tetrahydroor perhydro forms) of the above-mentioned heteroaryl groups. Exemplaryheterocyclyl groups include morpholino, isochromanyl, chromanyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,indolinyl, isoindolinyl, di- and tetrahydrofuranyl, di- andtetrahydrothienyl, di- and tetrahydrooxazolyl, di- andtetrahydroisoxazolyl, di- and tetrahydrooxadiazolyl (1,2,5- and 1,2,3-),dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, di- andtetrahydrotriazolyl (1,2,3- and 1,2,4-), di- and tetrahydrothiazolyl,di- and tetrahydrothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and1,2,5-), di- and tetrahydropyridyl, di- and tetrahydropyrimidinyl, di-and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4-,and 1,3,5-), di- and tetrahydrobenzofuranyl (1- and 2-), di- andtetrahydroindolyl, di- and tetrahydroisoindolyl, di- andtetrahydrobenzothienyl (1- and 2), di- and tetrahydro-1H-indazolyl, di-and tetrahydrobenzimidazolyl, di- and tetrahydrobenzoxazolyl, di- andtetrahydroindoxazinyl, di- and tetrahydrobenzisoxazolyl, di- andtetrahydrobenzothiazolyl, di- and tetrahydrobenzisothiazolyl, di- andtetrahydrobenzotriazolyl, di- and tetrahydroquinolinyl, di- andtetrahydroisoquinolinyl, di- and tetrahydrobenzodiazinyl, di- andtetrahydroquinoxalinyl, di- and tetrahydroquinazolinyl, di- andtetrahydrobenzotriazinyl (1,2,3- and 1,2,4-), di- andtetrahydropyridazinyl, di- and tetrahydrophenoxazinyl, di- andtetrahydrothiazolopyridinyl (such as4,5,6-7-tetrahydro[1,3]thiazolo[5,4-c]pyridinyl or4,5,6-7-tetrahydro[1,3]thiazolo[4,5-c]pyridinyl, e.g.,4,5,6-7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl or4,5,6-7-tetrahydro[1,3]thiazolo[4,5-c]pyridin-2-yl), di- andtetrahydropyrrolothiazolyl (such as5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazolyl), di- andtetrahydrophenothiazinyl, di- and tetrahydroisobenzofuranyl, di- andtetrahydrochromenyl, di- and tetrahydroxanthenyl, di- andtetrahydrophenoxathiinyl, di- and tetrahydropyrrolizinyl, di- andtetrahydroindolizinyl, di- and tetrahydroindazolyl, di- andtetrahydropurinyl, di- and tetrahydroquinolizinyl, di- andtetrahydrophthalazinyl, di- and tetrahydronaphthyridinyl (1,5-, 1,6-,1,7-, 1,8-, and 2,6-), di- and tetrahydrocinnolinyl, di- andtetrahydropteridinyl, di- and tetrahydrocarbazolyl, di- andtetrahydrophenanthridinyl, di- and tetrahydroacridinyl, di- andtetrahydroperimidinyl, di- and tetrahydrophenanthrolinyl (1,7-, 1,8-,1,10-, 3,8-, and 4,7-), di- and tetrahydrophenazinyl, di- andtetrahydrooxazolopyridinyl, di- and tetrahydroisoxazolopyridinyl, di-and tetrahydropyrrolooxazolyl, and di- and tetrahydropyrrolopyrrolyl.Exemplary 5- or 6-membered heterocyclyl groups include morpholino,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- andtetrahydrooxazolyl, di- and tetrahydroisoxazolyl, di- andtetrahydrooxadiazolyl (1,2,5- and 1,2,3-), dihydropyrrolyl,dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl (1,2,3-and 1,2,4-), di- and tetrahydrothiazolyl, di- andtetrahydroisothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and1,2,5-), di- and tetrahydropyridyl, di- and tetrahydropyrimidinyl, di-and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4-,and 1,3,5-), and di- and tetrahydropyridazinyl.

The term “N-heterocycloalkylene” as used herein means a heterocyclylgroup as defined above which contains at least one ring nitrogen atomand in which one hydrogen atom has been removed from the same carbonatom resulting in a geminal diradical. In addition to the at least onering nitrogen atom, the N-heterocycloalkylene may contain 1, 2, or 3further ring heteroatoms selected from the group consisting of O, S, orN. Preferably, in each ring of the N-heterocycloalkylene group themaximum number of O atoms is 1, the maximum number of S atoms is 1, andthe maximum total number of O and S atoms is 2. Preferably, theN-heterocycloalkylene is monocyclic and contains 1, 2 or 3 ring nitrogenatoms and optionally does not contain O or S ring atoms. The term“N-heterocycloalkylene” is also meant to encompass partially orcompletely hydrogenated forms (such as dihydro, tetrahydro or perhydroforms) of the above-mentioned heteroaryl groups (preferably partially orcompletely hydrogenated forms of the above-mentioned monocyclicheteroaryl groups) which contain at least one ring nitrogen atom and inwhich one hydrogen atom has been removed from the same carbon atomresulting in a geminal diradical. Thus, according to the invention, anN-heterocycloalkylene may be saturated or unsaturated (i.e., it maycontain one or more double bonds within the ring) but cannot bearomatic. Exemplary N-heterocycloalkylene groups include azetidinylene(N at position 2 or 3 relative to the diradical carbon atom),pyrrolidinylene (N at position 2 or 3), pyrazolidinylene (Ns atpositions 2 and 3 or 3 and 4), imidazolidinylene (Ns at positions 2 and4 or 2 and 5), triazolidinylene (Ns at positions 2, 3, and 4 or 2, 3,and 5), piperidinylene (N at position 2, 3, or 4), piperazinylene (Ns atpositions 2 and 5), di-, tetra-, and hexahydropyridazinylene (Ns atposition 2 and 3 or 3 and 4), di-, tetra-, and hexahydropyrimidinylene(Ns at positions 2 and 4 or 3 and 5), di- and tetrahydrotriazinylene,azepanylene (N at position 2, 3, or 4), diazepanylene (Ns at positions 2and 3; 2 and 4; 2 and 5; 2 and 6; 2 and 7; 3 and 4; 3 and 5; 3 and 6; or4 and 5), triazepanylene (Ns at positions 2, 3, and 4; 2, 3, and 5; 2,3, and 6; 2, 3, and 7; 2, 4, and 5; 2, 4, and 6; 2, 4, and 7; 2, 5, and6; 2, 5, and 7; 3, 4, and 5; or 3, 4, and 6), azocanylene (N at position2, 3, 4, or 5), diazocanylene (Ns at positions 2 and 3; 2 and 4; 2 and5; 2 and 6; 2 and 7; 2 and 8; 3 and 4; 3 and 5; 3 and 6; 3 and 7; 4 and5; or 4 and 6), triazocanylene (Ns at position 2, 3, and 4; 2, 3, and 5;2, 3, and 6; 2, 3, and 7; 2, 3, and 8; 2, 4, and 5; 2, 4, and 6; 2, 4,and 7; 2; 4, and 8; 2, 5, and 6; 2, 5, and 7; 2, 5, and 8; 2, 6, and 7;3, 4, and 5; 3, 4, and 6; 3, 4, and 7; 3, 5, and 6; 3, 5, and 7; or 4,5, and 6), and morpholinylene.

The term “monocyclic 4- to 10-membered N-heterocycloalkylene” as usedherein means that the 4 to 10 members of the N-heterocycloalkylene areconnected in such a manner that they form a single ring (e.g.piperidinylene). Thus, with the exception of the spiro carbon atom ofring A (which belongs to both ring A and the quinoxaline moiety) theremaining 3 to 9 ring atoms of ring A only belong to ring A, i.e, thering atoms of ring A do not belong to any further ring. Therefore,according to the invention, the term “monocyclic 4- to 10-memberedN-heterocycloalkylene” does not encompass polycyclic (e.g., bi- ortricyclic) structures (such as indolinylene), wherein at least two ringatoms belong to more than one ring.

The term “O/S-heterocycloalkylene” as used herein means a heterocyclylgroup as defined above which contains at least one ring heteroatomselected from oxygen and sulfur and in which one hydrogen atom has beenremoved from the same carbon atom resulting in a geminal diradical.Preferably, each of the ring atoms of the O/S-heterocycloalkylene isselected from the group consisting of carbon, oxygen, and sulfur (i.e.,the O/S-heterocycloalkylene preferably does not contain heteroatomsother than oxygen or sulfur). Preferably, in each ring of theO/S-heterocycloalkylene group the maximum number of O atoms is 2 or 1,the maximum number of S atoms is 2 or 1, and the maximum total number ofO and S atoms is 2. Preferably, the O/S-heterocycloalkylene ismonocyclic and contains 1 or 2 ring heteroatoms selected from oxygen andsulfur and optionally does not contain ring heteroatoms other thanoxygen or sulfur. The term “O/S-heterocycloalkylene” is also meant toencompass partially or completely hydrogenated forms (such as dihydro,tetrahydro or perhydro forms) of the above-mentioned heteroaryl groups(preferably partially or completely hydrogenated forms of theabove-mentioned monocyclic heteroaryl groups) which contain at least onering heteroatom selected from oxygen and sulfur and in which onehydrogen atom has been removed from the same carbon atom resulting in ageminal diradical. Thus, according to the invention, anO/S-heterocycloalkylene may be saturated or unsaturated (i.e., it maycontain one or more double bonds within the ring) but cannot bearomatic. Exemplary O/S-heterocycloalkylene groups include oxetanylene(O at position 2 or 3), thietanylene (S at position 2 or 3), di- andtetrahydrofuranylene (O at position 2 or 3), di- andtetrahydrothienylene (S at position 2 or 3), di- andtetrahydropyranylene (O at position 2, 3, or 4), di- andtetrahydrothiopyranylene (S at position 2, 3, or 4), oxepanylene (O atposition 2, 3, or 4), thiepanylene (S at position 2, 3, or 4),oxocanylene (O at position 2, 3, 4, or 5), thiocanylene (S at position2, 3, 4, or 5), dioxolanylene (Os at positions 2 and 4 or 2 and 5),dithiolanylene (Ss at positions 2 and 3; 2 and 4; 2 and 5; or 3 and 4),oxathiolanylene (O at position 2 and S at position 3 or 4; O at position4 and S at position 2; or O at position 2 and S at position 5),dioxanylene (Os at positions 2 and 4; 2 and 5; 2 and 6; or 3 and 5),dithianylene (Ss at positions 2 and 3; 2 and 4; 2 and 5; 2 and 6; 3 and4; or 3 and 5), oxathianylene (O at position 2 and S at position 4, 5,or 6; O at position 3 and S at position 5 or 6; or S at position 2 and Oat position 4), dioxepanylene (Os at positions 2 and 4; 2 and 5; 2 and6; 2 and 7; 3 and 5; or 3 and 6), dithiepanylene (Ss at positions 2 and3; 2 and 4; 2 and 5; 2 and 6; 2 and 7; 3 and 4; 3 and 5; 3 and 6; or 4and 5), oxathiepanylene (O at position 2 and S at position 4, 5, 6, or7; O at position 3 and S at position 5, 6, or 7; O at position 4 and Sat position 6 or 7; or S at position 2 and O at position 4),dioxocanylene (Os at positions 2 and 4; 2 and 5; 2 and 6; 2 and 7; 2 and8; 3 and 5; 3 and 6; 3 and 7; or 4 and 6), dithiocanylene (Ss atpositions 2 and 3; 2 and 4; 2 and 5; 2 and 6; 2 and 7; 2 and 8; 3 and 4;3 and 5; 3 and 6; 3 and 7; 4 and 5; or 4 and 6), and oxathiocanylene (Oat position 2 and S at position 2, 3, 4, 5, 6, or 7; O at position 3 andS at position 5, 6, 7, or 8; O at position 4 and S at position 6, 7, or8; S at position 2 and O at position 4 or 5; S at position 3 and O atposition 5).

The term “monocyclic 4- to 10-membered O/S-heterocycloalkylene” as usedherein means that the 4 to 10 members of the O/S-heterocycloalkylene areconnected in such a manner that they form a single ring (e.g.tetrahydropyranylene). Thus, with the exception of the spiro carbon atomof ring A (which belongs to both ring A and the quinoxaline moiety) theremaining 3 to 9 ring atoms of ring A only belong to ring A, i.e, thering atoms of ring A do not belong to any further ring. Therefore,according to the invention, the term “monocyclic 4- to 10-memberedO/S-heterocycloalkylene” does not encompass polycyclic (e.g., bi- ortricyclic) structures (such as 3,4-dihydro-2H-chromenylene), wherein atleast two ring atoms belong to more than one ring.

The term “cycloalkylene” as used herein means a cycloalkyl group asdefined above in which one hydrogen atom has been removed from the samecarbon atom resulting in a geminal diradical. Preferably, thecycloalkylene is monocyclic. The term “cycloalkylene” is also meant toencompass partially or completely hydrogenated forms (such as dihydro,tetrahydro or perhydro forms) of the above-mentioned aryl groups(preferably partially or completely hydrogenated forms of theabove-mentioned monocyclic aryl groups) in which one hydrogen atom hasbeen removed from the same carbon atom resulting in a geminal diradical.Thus, according to the invention, a cycloalkylene may be saturated orunsaturated (i.e., it may contain one or more double bonds within thering) but cannot be aromatic. Exemplary cycloalkylene groups includecyclohexylene, cycloheptylene, cyclopropylene, cyclobutylene,cyclopentylene, cyclooctylene, cyclohexenylene, cycloheptenylene,cyclopropenylene, cyclobutenylene, cyclopentenylene, andcyclooctenylene.

The term “monocyclic 3- to 10-membered cycloalkylene” as used hereinmeans that the 3 to 10 ring carbon atoms of the cycloalkylene areconnected in such a manner that they form a single ring (e.g.cyclohexylene). Thus, with the exception of the spiro carbon atom ofring A (which belongs to both ring A and the quinoxaline moiety) theremaining 2 to 9 ring carbon atoms of ring A only belong to ring A, i.e,the ring carbon atoms of ring A do not belong to any further ring.Therefore, according to the invention, the term “monocyclic 3- to10-membered cycloalkylene” does not encompass polycyclic (e.g., bi- ortricyclic) structures (such as indanylene), wherein at least two ringatoms belong to more than one ring.

The term “halogen” or “halo” means fluoro, chloro, bromo, or iodo.

The term “azido” means N₃.

The term “any two R⁹ which are bound to the same carbon atom of ring Amay join together to form ═X” as used herein means that two monoradicals(i.e., R⁹) when substituting in total 2 hydrogen atoms bound to only onering carbon atom of ring A can form the diradical ═X. For example,according to the invention, ring A being

encompasses not only (1) the possibility that both R⁹ groups aremonoradicals independently selected from the particular moietiesspecified herein (e.g., methyl, —Cl, —OH, or —C(O)CH₃)) but also (2) thepossibility that the two R⁹ groups join together to form the diradical═X resulting in a ring A having the following formula:

wherein X is O, S, or N(R¹⁴). Similar terms such as “any two R³⁰ whichare bound to the same carbon atom of a cycloalkyl or heterocyclyl groupmay join together to form ═X¹” as used herein are to be interpreted inan analogous manner.

The term “optionally substituted” indicates that one or more (such as 1to the maximum number of hydrogen atoms bound to a group, e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to3, or 1 or 2) hydrogen atom(s) may be replaced with a group (i.e., a1^(st) level substituent) different from hydrogen such as alkyl(preferably, C₁₋₆ alkyl), alkenyl (preferably, C₂₋₆ alkenyl), alkynyl(preferably, C₂₋₆ alkynyl), aryl (preferably, 3- to 14-membered aryl),heteroaryl (preferably, 3- to 14-membered heteroaryl), cycloalkyl(preferably, 3- to 14-membered cycloalkyl), heterocyclyl (preferably, 3-to 14-membered heterocyclyl), halogen, —CN, azido, —NO₂, —OR⁷¹,—N(R⁷²)(R⁷³), —ON(R⁷²)(R⁷³), —N⁺(—O⁻)(R⁷²)(R⁷³), —S(O)₀₋₂R⁷¹,—S(O)₀₋₂OR⁷¹, —OS(O)₀₋₂R⁷¹, —OS(O)₀₋₂R⁷¹, —S(O)₀₋₂N(R⁷²)(R⁷³),—OS(O)₀₋₂N(R⁷²)(R⁷³), —N(R⁷¹)S(O)₀₋₂R⁷¹, —NR⁷¹S(O)₀₋₂OR⁷¹,—NR⁷¹S(O)₀₋₂N(R⁷²)(R⁷³), —C(═X¹)R⁷¹, —C(═X¹)X¹R⁷¹, —X¹C(═X¹)R⁷¹, and—X¹C(═X¹)X¹R⁷¹, and/or any two 1^(st) level substituents which are boundto the same carbon atom of a cycloalkyl or heterocyclyl group may jointogether to form ═X¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups of the 1^(st) levelsubstituent may themselves be substituted by one, two or threesubstituents (i.e., a 2^(nd) level substituent) selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 14-memberedaryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to14-membered heterocyclyl, halogen, —CF₃, —CN, azido, —NO₂, —OR⁸¹,—N(R⁸²)(R⁸³), —ON(R⁸²)(R⁸³), —N⁺(—O⁻)(R⁸²)(R⁸³), —S(O)₀₋₂R⁸¹,—S(O)₀₋₂OR⁸¹, —OS(O)₀₋₂R⁸¹, —OS(O)₀₋₂OR⁸¹, —S(O)₀₋₂N(R⁸²)(R⁸³),—OS(O)₀₋₂N(R⁸²)(R⁸³), —N(R⁸¹)S(O)₀₋₂R, —NR⁸¹S(O)₀₋₂OR⁸¹,—NR⁸¹S(O)₀₋₂N(R⁸²)(R⁸³), —C(═X²)R⁸¹, —C(═X²)X²R⁸¹, —X²C(═X²)R⁸¹, and—X²C(═X²)X²R⁸¹, and/or any two 2^(nd) level substituents which are boundto the same carbon atom of a cycloalkyl or heterocyclyl group may jointogether to form ═X², wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups of the2^(nd) level substituent is optionally substituted with one, two orthree substituents (i.e., a 3^(rd) level substituent) independentlyselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl),—N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z),—C(═O)OH, —C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z),—NHC(═O)(C₁₋₃ alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3^(rd) levelsubstituents which are bound to the same carbon atom of a cycloalkyl orheterocyclyl group may join together to form ═O, ═S, ═NH, or ═N(C₁₋₃alkyl);

wherein

R⁷¹, R⁷², and R⁷³ are independently selected from the group consistingof —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 7-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl,or R⁷² and R⁷³ may join together with the nitrogen atom to which theyare attached to form a 5- or 6-membered ring, which is optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl;R⁸¹, R⁸², and R⁸³ are independently selected from the group consistingof —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3- to 6-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 6-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl,or R⁸² and R⁸³ may join together with the nitrogen atom to which theyare attached to form a 5- or 6-membered ring, which is optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl;X¹ and X² are independently selected from O, S, and NR⁸⁴, wherein R⁸⁴ is—H or C₁₋₃ alkyl.

Typical 1^(st) level substituents are preferably selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 14-membered(such as 5- or 6-membered) aryl, 3- to 14-membered (such as 5- or6-membered) heteroaryl, 3- to 14-membered (such as 3- to 7-membered)cycloalkyl, 3- to 14-membered (such as 3- to 7-membered) heterocyclyl,halogen, —CN, azido, —NO₂, —OR⁷¹, —N(R⁷²)(R⁷³), —S(O)₀₋₂R⁷¹,—S(O)₀₋₂OR⁷¹, —OS(O)₀₋₂R⁷¹, —OS(O)₀₋₂OR⁷¹, —S(O)₀₋₂N(R⁷²)(R⁷³),—OS(O)₀₋₂N(R⁷²)(R⁷³), —N(R⁷¹)S(O)₀₋₂R⁷, —NR⁷¹S(O)₀₋₂OR¹OR, —C(═X¹)R⁷¹,—C(═X¹)X¹R⁷¹, —X¹C(═X¹)R⁷¹, and —X¹C(═X¹)X¹R⁷¹, such as C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl,halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —S(C₁₋₃ alkyl),—NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH, —C(═O)O(C₁₋₃ alkyl),—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃ alkyl),—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl; X¹ is independently selected from O, S, NH andN(CH₃); and R⁷¹, R⁷², and R⁷³ are as defined above or, preferably, areindependently selected from the group consisting of —H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclyl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with one,two or three substituents selected from the group consisting of C₁₋₃alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —S(C₁₋₃alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH, —C(═O)O(C₁₋₃ alkyl),—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃ alkyl),—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl; or R⁷² and R⁷³ may join together with the nitrogenatom to which they are attached to form a 5- or 6-membered ring, whichis optionally substituted with one, two or three substituents selectedfrom the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido,—NO₂, —OH, —O(C₁₋₃ alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl),—N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z),—C(═O)OH, —C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z),—NHC(═O)(C₁₋₃ alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl.

Typical 2^(nd) level substituents are preferably selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or6-membered heterocyclyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl. Particularly preferred2^(nd) level substituents include 4-morpholinyl, homomorpholinyl,4-piperidinyl, homopiperidinyl (i.e., azepanyl, in particular4-azepanyl), 4-piperazinyl, homopiperazinyl (i.e., diazepanyl, inparticular 2,4-diazepanyl), N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, —CH₂CH₂OCH₃, —OCH₂CH₂OCH₃,—CH₂CH₂NH_(2-z)(CH₃)_(z), —OCH₂CH₂NH_(2-z)(CH₃)_(z), —CF₃, and —OCF₃.

Typical 3^(rd) level substituents are preferably selected from the groupconsisting of phenyl, furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,partially and completely hydrogenated forms of the forgoing groups,morpholino, C₁₋₃ alkyl, halogen, —CF₃, —OH, —OCH₃, —SCH₃,—NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, wherein z is 0, 1, or 2.

The term “aromatic” as used in the context of hydrocarbons means thatthe whole molecule has to be aromatic. For example, if a monocyclic arylis hydrogenated (either partially or completely) the resultinghydrogenated cyclic structure is classified as cycloalkyl for thepurposes of the present invention. Likewise, if a bi- or polycyclic aryl(such as naphthyl) is hydrogenated the resulting hydrogenated bi- orpolycyclic structure (such as 1,2-dihydronaphthyl) is classified ascycloalkyl for the purposes of the present invention (even if one ring,such as in 1,2-dihydronaphthyl, is still aromatic). A similardistinction is made within the present application between heteroaryland heterocyclyl. For example, indolinyl, i.e., a dihydro variant ofindolyl, is classified as heterocyclyl for the purposes of the presentinvention, since only one ring of the bicyclic structure is aromatic andone of the ring atoms is a heteroatom.

The phrase “partially hydrogenated form” of an unsaturated compound orgroup as used herein means that part of the unsaturation has beenremoved by formally adding hydrogen to the initially unsaturatedcompound or group without removing all unsaturated moieties. The phrase“completely hydrogenated form” of an unsaturated compound or group isused herein interchangeably with the term “perhydro” and means that allunsaturation has been removed by formally adding hydrogen to theinitially unsaturated compound or group. For example, partiallyhydrogenated forms of a 5-membered heteroaryl group (containing 2 doublebonds in the ring, such as furan) include dihydro forms of said5-membered heteroaryl group (such as 2,3-dihydrofuran or2,5-dihydrofuran), whereas the tetrahydro form of said 5-memberedheteroaryl group (e.g., tetrahydrofuran, i.e., THF) is a completelyhydrogenated (or perhydro) form of said 5-membered heteroaryl group.Likewise, for a 6-membered heteroaryl group having 3 double bonds in thering (such as pyridyl), partially hydrogenated forms include di- andtetrahydro forms (such as di- and tetrahydropyridyl), whereas thehexahydro form (such as piperidinyl in case of the heteroaryl pyridyl)is the completely hydrogenated (or perhydro) derivative of said6-membered heteroaryl group. Consequently, a hexahydro form of an arylor heteroaryl can only be considered a partially hydrogenated formaccording to the present invention if the aryl or heteroaryl contains atleast 4 unsaturated moieties consisting of double and triple bondsbetween ring atoms.

The term “optional” or “optionally” as used herein means that thesubsequently described event, circumstance or condition may or may notoccur, and that the description includes instances where said event,circumstance, or condition occurs and instances in which it does notoccur.

“Isomers” are compounds having the same molecular formula but differ instructure (“structural isomers”) or in the geometrical positioning ofthe functional groups and/or atoms (“stereoisomers”). “Enantiomers” area pair of stereoisomers which are non-superimposable mirror-images ofeach other. A “racemic mixture” or “racemate” contains a pair ofenantiomers in equal amounts and is denoted by the prefix (±).“Diastereomers” are stereoisomers which are non-superimposablemirror-images of each other. “Tautomers” are structural isomers of thesame chemical substance that spontaneously interconvert with each other,even when pure.

In case a structural formula shown in the present application can beinterpreted to encompass more than one isomer, said structural formula,unless explicitly stated otherwise, encompasses all possible isomers,and hence each individual such isomer. For example, a compound offormula (I), wherein ring A is

encompasses both isomers, i.e., the isomer having the following formula(B1) and the isomer having the following formula (B2):

“Polymorphism” as referred to herein means that a solid material (suchas a compound) is able to exist in more than one form or crystallinestructure, i.e., “polymorphic modifications” or “polymorphic forms”. Theterms “polymorphic modifications”, “polymorphic forms”, and “polymorphs”are used interchangeable in the present invention. According to thepresent invention, these “polymorphic modifications” include crystallineforms, amorphous forms, solvates, and hydrates. Mainly, the reason forthe existence of different polymorphic forms lies in the use ofdifferent conditions during the crystallization process, such as thefollowing:

-   -   solvent effects (the packing of crystal may be different in        polar and nonpolar solvents);    -   certain impurities inhibiting growth pattern and favor the        growth of a metastable polymorphs;    -   the level of supersaturation from which material is crystallized        (in which generally the higher the concentration above the        solubility, the more likelihood of metastable formation);    -   temperature at which crystallization is carried out;    -   geometry of covalent bonds (differences leading to        conformational polymorphism);    -   change in stirring conditions.

Polymorphic forms may have different chemical, physical, and/orpharmacological properties, including but not limited to, melting point,X-ray crystal and diffraction pattern, chemical reactivity, solubility,dissolution rate, vapor pressure, density, hygroscopicity, flowability,stability, compactability, and bioavailability. Polymorphic forms mayspontaneously convert from a metastable form (unstable form) to thestable form at a particular temperature. According to Ostwald's rule, ingeneral it is not the most stable but the least stable polymorph thatcrystallizes first. Thus, quality, efficacy, safety, processabilityand/or manufacture of a chemical compound, such as a compound of thepresent invention, can be affected by polymorphism. Often, the moststable polymorph of a compound (such as a compound of the presentinvention) is chosen due to the minimal potential for conversion toanother polymorph. However, a polymorphic form which is not the moststable polymorphic form may be chosen due to reasons other thanstability, e.g. solubility, dissolution rate, and/or bioavailability.

The term “crystalline form” of a material as used herein means that thesmallest components (i.e., atoms, molecule or ions) of said materialform crystal structures. A “crystal structure” as referred to hereinmeans a unique three-dimensional arrangement of atoms or molecules in acrystalline liquid or solid and is characterized by a pattern, a set ofatoms arranged in a particular manner, and a lattice exhibitinglong-range order and symmetry. A lattice is an array of points repeatingperiodically in three dimensions and patterns are located upon thepoints of a lattice. The subunit of the lattice is the unit cell. Thelattice parameters are the lengths of the edges of a unit cell and theangles between them. The symmetry properties of the crystal are embodiedin its space group. In order to describe a crystal structure thefollowing parameters are required: chemical formula, lattice parameters,space group, the coordinates of the atoms and occupation number of thepoint positions.

The term “amorphous form” of a material as used herein means that thesmallest components (i.e., atoms, molecule or ions) of said material arenot arranged in a lattice but are arranged randomly. Thus, unlikecrystals in which a short-range order (constant distances to the nextneighbor atoms) and a long-range order (periodical repetition of a basiclattice) exist, only a short-range order exists in an amorphous form.

The term “complex of a compound” as used herein refers to a compound ofhigher order which is generated by association of the compound withother one or more other molecules. Exemplary complexes of a compoundinclude, but are not limited to, solvates, clusters, and chelates ofsaid compound.

The term “solvate” as used herein refers to an addition complex of adissolved material in a solvent (such as an organic solvent (e.g., analiphatic alcohol (such as methanol, ethanol, n-propanol, isopropanol),acetone, acetonitrile, ether, and the like), water or a mixture of twoor more of these liquids), wherein the addition complex exists in theform of a crystal or mixed crystal. The amount of solvent contained inthe addition complex may be stoichiometric or non-stoichiometric. A“hydrate” is a solvate wherein the solvent is water.

In isotopically labeled compounds one or more atoms are replaced by acorresponding atom having the same number of protons but differing inthe number of neutrons. For example, a hydrogen atom may be replaced bya deuterium atom. Exemplary isotopes which can be used in the compoundsof the present invention include deuterium, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F,³²S, ³⁶Cl, and ¹²⁵I.

The term “half-life” relates to the period of time which is needed toeliminate half of the activity, amount, or number of molecules. In thecontext of the present invention, the half-life of a compound of formula(I) is indicative for the stability of said compound.

The terms “patient”, “individual”, or “animal” relate to multicellularanimals, such as vertebrates. For example, vertebrates in the context ofthe present invention are mammals, birds (e.g., poultry), reptiles,amphibians, bony fishes, and cartilaginous fishes, in particulardomesticated animals of any of the foregoing as well as animals (inparticular vertebrates) in captivity such as animals (in particularvertebrates) of zoos. Mammals in the context of the present inventioninclude, but are not limited to, humans, non-human primates,domesticated mammals, such as dogs, cats, sheep, cattle, goats, pigs,horses etc., laboratory mammals such as mice, rats, rabbits, guineapigs, etc. as well as mammals in captivity such as mammals of zoos. Theterm “animal” as used herein also includes humans. Particularnon-limiting examples of birds include domesticated poultry, and includebirds such as chickens, turkies, ducks, geese, guinea fowl, pigeons,pheasants etc; while particular non-limiting examples of bony orcartilaginous fish include those suitable for cultivation byaquiculture, and include bony fish such as salmon, trout, perch, carp,cat-fish, etc.

Compounds

In one aspect, the present invention provides a compound selected fromthe group consisting of a spiroquinoxaline derivative having the generalformula (I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof,whereinE is —N(R⁶)—;L is selected from the group consisting of C₁₋₁₀ alkylene, C₂₋₁₀alkenylene, C₂₋₁₀ alkynylene, 1,1-(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—,wherein each of a and b is independently selected from an integerbetween 0 and 3, and —(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is aninteger between 1 and 6, n is an integer between 0 and 3, o is aninteger between 1 and 3, wherein if n is 0 then o is 1; Y isindependently selected from O, S, and —N(R⁷)—; and each of the C₁₋₁₀alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, and —(CH₂)_(n)— groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, or —(CH₂)_(n)— group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;G is phenyl, optionally substituted with 1, 2, 3, 4 or 5 independentlyselected R⁸;ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene, amonocyclic 4- to 10-membered O/S-heterocycloalkylene, or a monocyclic 3-to 10-membered cycloalkylene, wherein each of the N-heterocycloalkylene,O/S-heterocycloalkylene, and cycloalkylene groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹;R¹ is H;R², R³, R⁴, and R⁵ are independently selected from the group consistingof —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³),—N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰;or R² and R³ may join together with the atoms to which they are attachedto form a ring which is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the ring, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1to 3, or 1 or 2) independently selected R³⁰; R³ and R⁴ may join togetherwith the atoms to which they are attached to form a ring which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰; and/or R⁴ and R⁵ may join together with theatoms to which they are attached to form a ring which is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁶ is H;R⁷ is selected from the group consisting of —H, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R⁸ is, in each case, selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen,—CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹,—S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁹ is, when substituting a hydrogen atom bound to a ring carbon atom,independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN,azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹,—OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹,—C(═X)XR¹¹, —XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groupsis optionally substituted with one or more (such as 1 to the maximumnumber of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰, and/or any two R⁹ which are bound to thesame carbon atom of ring A may join together to form ═X; or R⁹ is, whensubstituting a hydrogen atom bound to a ring nitrogen atom,independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, —OR¹¹,—N(R¹²)(R¹³), —S(O)₁₋₂R¹¹, —S(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —N¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹,—C(═X)XR¹¹, —N(R¹⁴)C(═X)R¹¹, and —N(R¹⁴)C(═X)XR¹¹, wherein each of thealkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclylgroups is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R³⁰; or R⁹ is, when bound to a ringsulfur atom of ring A, independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,—OR¹¹, and ═O, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups is optionallysubstituted with one or more independently selected R³⁰;X is independently selected from O, S, and N(R¹⁴);R¹¹ is, in each case, selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹² and R¹³ are, in each case, independently selected from the groupconsisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl, or R¹² and R¹³ may join together with the nitrogenatom to which they are attached to form the group —N═CR¹⁵R¹⁶, whereineach of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R¹⁴ is independently selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR¹¹,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹⁵ and R¹⁶ are independently selected from the group consisting of —H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and—NH_(y)R²⁰ _(2-y), or R¹⁵ and R¹⁶ may join together with the atom towhich they are attached to form a ring which is optionally substitutedwith one or more (such as 1 to the maximum number of hydrogen atomsbound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;y is an integer from 0 to 2;R²⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclylgroups is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R³⁰; and R³⁰ is a 1^(st) levelsubstituent and is, in each case, independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR⁷¹, —N(R⁷²)(R⁷³),—S(O)₀₋₂R⁷¹, —S(O)₁₋₂OR⁷¹, —OS(O)₁₋₂R⁷¹, —OS(O)₁₋₂OR⁷¹,—S(O)₁₋₂N(R⁷²)(R⁷³), —OS(O)₁₋₂N(R⁷²)(R⁷³), —N(R⁷¹)S(O)₁₋₂R⁷¹,—NR⁷¹S(O)₁₋₂OR⁷¹, —NR⁷¹S(O)₁₋₂N(R⁷²)(R⁷³), —C(═X¹)R⁷¹, —C(═X¹)X¹R⁷¹,—X¹C(═X¹)R⁷¹, and —X¹C(═X¹)X¹R⁷¹, and/or any two R³⁰ which are bound tothe same carbon atom of a cycloalkyl or heterocyclyl group may jointogether to form ═X¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups being a 1^(st) levelsubstituent is optionally substituted by one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, or heterocyclyl group being a 1^(st) levelsubstituent, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) 2^(nd) level substituents,wherein said 2^(nd) level substituent is, in each case, independentlyselected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF₃,—CN, azido, —NO₂, —OR⁸¹, —N(R⁸²)(R⁸³), —S(O)₀₋₂R⁸¹, —S(O)₁₋₂OR⁸¹,—OS(O)₁₋₂R⁸¹, —OS(O)₁₋₂OR⁸¹, —S(O)₁₋₂N(R⁸²)(R⁸³), —OS(O)₁₋₂N(R⁸²)(R⁸³),—N(R⁸¹)S(O)₁₋₂R⁸¹, —NR⁸¹S(O)₁₋₂OR⁸¹, —NR⁸¹S(O)₁₋₂N(R⁸²)(R⁸³),—C(═X²)R⁸¹, —C(═X²)X²R⁸¹, —X²C(═X²)R⁸¹, and —X²C(═X²)X²R⁸¹, and/or anytwo 2^(nd) level substituents which are bound to the same carbon atom ofa cycloalkyl or heterocyclyl group being a 1^(st) level substituent mayjoin together to form ═X², wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3-to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl groupsbeing a 2^(nd) level substituent is optionally substituted with one ormore (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to14-membered heteroaryl, 3- to 14-membered cycloalkyl, or 3- to14-membered heterocyclyl group being a 2^(nd) level substituent, e.g.,1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4,or 1 to 3, or 1 or 2) 3^(rd) level substituents, wherein said 3^(rd)level substituent is, in each case, independently selected from thegroup consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH,—O(C₁₋₃ alkyl), —OCF₃, —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3^(rd) levelsubstituents which are bound to the same carbon atom of a 3- to14-membered cycloalkyl or heterocyclyl group being a 2^(nd) levelsubstituent may join together to form ═O, ═S, ═NH, or ═N(C₁₋₃ alkyl);whereinR⁷¹, R⁷², and R⁷³ are independently selected from the group consistingof —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 7-membered heterocyclyl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl;R⁸¹, R⁸², and R⁸³ are independently selected from the group consistingof —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3- to 6-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 6-membered heterocyclyl, wherein each of the C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl; andX¹ and X² are independently selected from O, S, and N(R⁸⁴), whereinR^(s4) is —H or C₁₋₃ alkyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (II)

wherein R¹ to R⁵, E, L and G are as defined above or below and ring A(i) is a N-heterocycloalkylene which contains 1 ring nitrogen atom andis 4- to 8-membered (preferably 5-, 6- or 7-membered, more preferably 6-or 7-membered) or which contains 2 or 3 ring nitrogen atoms and is 5- to8-membered, preferably 5-, 6- or 7-membered, more preferably 6- or7-membered; (ii) is a O/S-heterocycloalkylene which contains 1 ringoxygen or sulfur atom and is 4- to 8-membered (preferably 5-, 6- or7-membered, more preferably 6- or 7-membered) or which contains 2 ringheteroatoms selected from oxygen and sulfur and is 5- to 8-membered,preferably 5-, 6- or 7-membered, more preferably 6- or 7-membered; or(iii) is a cycloalkylene which is 3- to 8-membered, preferably 4-, 5-,6- or 7-membered, more preferably 6- or 7-membered. In one embodiment ofthe spiroquinoxaline derivative of formula (II), ring A as such isunsaturated (i.e., the members of ring A constitute 1, 2, or 3(preferably 1 or 2, most preferably 1) double bonds within the ring) butis not aromatic. In an alternative embodiment of the spiroquinoxalinederivative of formula (II), ring A is saturated (i.e., ring A as such isfree of unsaturation within the ring); however, if ring A is substitutedby one or more (such as 1 to the maximum number of hydrogen atoms boundto ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between1 to 5, 1 to 4, or 1 to 3, or 1 or 2) R⁹, R⁹ may be unsaturated (i.e.,may contain double and/or triple bonds and/or one or more (e.g., 1, 2.or 3) aromatic ring(s)). In any of the above embodiments of thespiroquinoxaline derivative of formula (II), the ring nitrogen, oxygen,and/or sulfur atoms of ring A (preferably all ring heteroatoms of ringA) are not at position alpha to the spiro carbon atom (i.e., in thisembodiment, preferably the two atoms of ring A positioned alpha to thespiro carbon atom are carbon atoms). In any of the above embodiments ofthe spiroquinoxaline derivative of formula (II), ring A may be selectedfrom the group consisting of piperidinylene, azepanylene (e.g.,homopiperidinylene), azetidinylene, pyrrolidinylene, azocanylene,pyrazolidinylene, hexahydropyridazinylene, hexahydropyrimidinylene,diazepanylene (e.g., homopiperazinylene), diazocanylene, triazepanylene,triazocanylene, di- and tetrahydropyranylene, di- andtetrahydrothiopyranylene, oxepanylene, thiepanylene, oxetanylene,thietanylene, di- and tetrahydrofuranylene, di- andtetrahydrothienylene, oxocanylene, thiocanylene, dithiolanylene,oxathiolanylene, dioxanylene, dithianylene, oxathianylene,dioxepanylene, dithiepanylene, oxathiepanylene, dioxocanylene,dithiocanylene, oxathiocanylene, cyclohexylene, cycloheptylene,cyclopropylene, cyclobutylene, cyclopentylene, cyclooctylene,cyclohexenylene, cycloheptenylene, cyclopentenylene, cyclooctenylene,and their regioisomers, each of which is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to ringA, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5,1 to 4, or 1 to 3, or 1 or 2) independently selected R⁹. In oneembodiment of the spiroquinoxaline derivative of formula (II), ring A isselected from the group consisting of 3- and 4-piperidinylene (N atposition 3 or 4 relative to the spiro carbon atom); 3- and4-azepanylene, 3-azetidinylene, 3-pyrrolidinylene, 3-, 4-, and5-azocanylene, 3,4-pyrazolidinylene, 3,4-hexahydropyridazinylene,3,5-hexahydropyrimidinylene, 3,4-, 3,5-, 3,6-, and 4,5-diazepanylene,3,4-, 3,5-, 3,6-, 3,7-, 4,5-, 4,6-diazocanylene, 3- and4-tetrahydropyranylene (O at position 3 or 4 relative to the spirocarbon atom); 3- and 4-tetrahydrothiopyranylene; 3- and 4-oxepanylene;3- and 4-thiepanylene; 3-oxetanylene; 3-thietanylene;3-tetrahydrofuranylene; 3-tetrahydrothienylene; 3-, 4-, and5-oxocanylene; 3-, 4-, and 5-thiocanylene; 3,4-dithiolanylene;3,4-oxathiolanylene; 3,5-dioxanylene; 3,4- and 3,5-dithianylene; 3,4-,3,5-, and 4,3-oxathianylene; 3,5- and 3,6-dioxepanylene; 3,4-, 3,5-,3,6-, and 4,5-dithiepanylene; 3,4-, 3,5-, 3,6-, 4,5-, 4,3-, and4,2-oxathiepanylene; 3,5-, 3,6-, 3,7-, and 4,6-dioxocanylene; 3,3-,3,4-, 3,5-, 3,6, 3,7-, 4,5-, and 4,6-dithiocanylene; and 3,4-, 3,5-,3,6-, 3,7-, 4,5-, 4,6, 4,7-, 4-3-, 5,4-, and 5,3-oxathiocanylene,cyclohexylene, cycloheptylene, cyclopropylene, cyclobutylene,cyclopentylene, and cyclooctylene, each of which is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹. In one embodiment of the spiroquinoxalinederivative of formula (II), ring A is selected from the group consistingof 4-piperidinylene, 3-piperidinylene, 3-azetidinylene,3-pyrrolidinylene, 4-azepanylene, 3-azepanylene, 5-azocanylene,4-azocanylene, 3-azocanylene, 3,6-diazepanylene (such as4-piperidinylene, 3-piperidinylene, 4-azepanylene, and 3-azepanylene),4-tetrahydropyranylene, 4-tetrahydrothiopyranylene,3-tetrahydropyranylene, 3-tetrahydrothiopyranylene, 4-oxepanylene,4-thiepanylene, 3-oxepanylene, 3-thiepanylene, 3-oxetanylene,3-thietanylene, 3-tetrahydrofuranylene, 3-tetrahydrothienylene,5-oxocanylene, 5-thiocanylene, 4-oxocanylene, 4-thiocanylene (such as-tetrahydropyranylene, 4-tetrahydrothiopyranylene,3-tetrahydropyranylene, 3-tetrahydrothiopyranylene, 4-oxepanylene,4-thiepanylene, 3-oxepanylene, and 3-thiepanylene), cyclohexylene,cycloheptylene, cyclopentylene, and cyclooctylene, each of which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹.

In any of the above embodiments of the spiroquinoxaline derivative offormula (II), ring A may be unsubstituted.

In any of the above embodiments of the spiroquinoxaline derivative offormula (II), wherein ring A is substituted with one or more (such as 1to the maximum number of hydrogen atoms bound to ring A, e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to3, or 1 or 2) independently selected R⁹, either (i) only one or more(preferably, 1, 2, or 3) ring heteroatoms of ring A (selected fromnitrogen, oxygen, and sulfur, wherein the maximum number of oxygen andsulfur atoms in ring A is preferably 2) are substituted withindependently selected R⁹, or (ii) only one or more (preferably, 1, 2,or 3) ring carbon atoms of ring A are substituted with independentlyselected R⁹, or (iii) one or more (preferably, 1, 2, or 3) ringheteroatoms (selected from nitrogen, oxygen, and sulfur, wherein themaximum number of oxygen and sulfur atoms in ring A is preferably 2) andone or more (preferably, 1, 2, or 3) ring carbon atoms of ring A (e.g.,1 or 2 ring heteroatoms and 1 or 2 ring carbon atoms) are substitutedwith independently selected R⁹. For example, if ring A contains 1 ringheteroatom (selected from nitrogen, oxygen, and sulfur), ring A may besubstituted (i) only at the ring heteroatom atom with R⁹ (preferably,the ring heteroatom is at position 3 if ring A is 4- or 5-membered; atposition 3 or 4 (preferably 4) if ring A is 6- or 7-membered; or atposition 3, 4, or 5 (preferably 4 or 5) if ring A is 8-membered); (ii)only at 1 or 2 ring carbon atoms of ring A each with 1 or 2independently selected R⁹; or (iii) at the ring heteroatom with R⁹(preferably, the ring heteroatom is at position 3 if ring A is 4- or5-membered; at position 3 or 4 (preferably 4) if ring A is 6- or7-membered; or at position 3, 4, or 5 (preferably 4 or 5) if ring A is8-membered) and at 1 or 2 ring carbon atoms of ring A each with 1 or 2independently selected R⁹.

In any of the above embodiments of the spiroquinoxaline derivative offormula (II), wherein R⁹ substitutes a hydrogen atom bound to a ringcarbon atom of ring A, each such R⁹ may be independently selected fromthe group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰, and/or any two R⁹ which are bound tothe same carbon atom of ring A may join together to form ═X. In any ofthe above embodiments of the spiroquinoxaline derivative of formula(II), wherein R⁹ substitutes a hydrogen atom bound to a ring carbon atomof ring A, each such R⁹ may be independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl,5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, 3-,5-, 6- or 7-membered heterocyclyl, halogen, —CN, —OR¹¹, —N(R¹²)(R¹³),—S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)SR¹¹,—C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹, —OC(═S)R¹¹,—N(R¹⁴)C(═O)N(R¹⁴)(R¹¹), and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein eachof the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-,6- or 7-membered heterocyclyl groups is optionally substituted with 1,2, or 3 independently selected R³⁰, and/or any two R⁹ which are bound tothe same carbon atom of ring A may join together to form ═O or ═S. Inone embodiment, each R⁹ when substituting a hydrogen atom bound to aring carbon atom of ring A is independently selected from the groupconsisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituentselected from the group consisting of —OH, —O(C₁₋₃ alkyl),—NH_(2-z)(CH₃)_(z), morpholinyl (e.g., 4-morpholinyl), piperazinyl(e.g., 1-piperazinyl), and N-methylpiperazinyl (e.g.,4-methylpiperazin-1-yl); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; cyclopropyl; 4-morpholinyl;homomorpholinyl; 4-piperidinyl; homopiperidinyl; 4-piperazinyl;homopiperazinyl; 4-methyl-piperazin-1-yl; N-methyl-homopiperazinyl;halogen; —CN; —OH; ═O; —O(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃alkyl); —S(O)₂(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl. In one embodiment, each R⁹ when substituting ahydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;tert-butyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—O(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —CH₂CF₃;—CH₂CHF₂; —CH₂CH₂F; —(CH₂)_(d)-(4-morpholinyl);—(CH₂)_(d)-(1-piperazinyl); —(CH₂)_(d)-(4-methylpiperazin-1-yl);4-morpholinyl; 4-piperazinyl; 4-methyl-piperazin-1-yl; halogen (inparticular, —F, —Cl, —Br); —NHC(═O)(C₁₋₃ alkyl optionally substitutedwith —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;halogen (in particular, —F, —Cl, —Br); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br);—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z);—S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃alkyl), wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl ismethyl, ethyl, propyl or isopropyl. In one embodiment, the ring carbonatoms of ring A are unsubstituted or each R⁹ substituting a hydrogenatom bound to a ring carbon atom is independently selected from thegroup consisting of C₁₋₄ alkyl (in particular methyl), —N(R¹²)(R¹³) (inparticular NH₂), and —N(R¹⁴)C(═O)R¹¹ (in particular NHC(O)CH₃). In oneembodiment, the ring carbon atoms of ring A are unsubstituted or onering carbon atom of ring A is substituted with one R⁹ being NH₂ or CH₃,or with two R⁹ being CH₃.

In any of the above embodiments of the spiroquinoxaline derivative offormula (II), wherein R⁹ substitutes a hydrogen atom bound to a ringnitrogen atom of ring A, each such R⁹ may be independently selected fromthe group consisting of C₁₋₁₂ alkyl (such as C₁₋₈ alkyl or C₁₋₆ alkyl),C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl,—OR¹¹, —N(R¹²)(R¹³), —S(O)₁₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—N(R¹⁴)C(═X)R¹¹, and —N(R¹⁴)C(═X)XR¹¹, wherein each of the C₁₋₁₂ alkyl(such as C₁₋₈ alkyl or C₁₋₆ alkyl), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₁₂ alkyl (such as C₁₋₈ alkyl or C₁₋₆alkyl), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In any of the above embodiments of the spiroquinoxaline derivativeof formula (II), wherein R⁹ substitutes a hydrogen atom bound to a ringnitrogen atom of ring A, each such R⁹ may be independently selected fromthe group consisting of C₁₋₁₂ alkyl (such as C₁₋₈ alkyl, C₁₋₆ alkyl orC₁₋₄ alkyl), C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, 3-, 5-, 6-or 7-membered heterocyclyl, —OR¹¹, —N(R¹²)(R¹³), —S(O)₁₋₂R¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —N¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R,—C(═O)OR¹¹, —C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹,—N(R¹⁴)C(═O)N(R¹⁴)(R¹¹), and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein eachof the C₁₋₁₂ alkyl (such as C₁₋₈ alkyl, C₁₋₆ alkyl, or C₁₋₄ alkyl), C₂₋₄alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3-,5-, 6- or 7-membered cycloalkyl, and 3-, 5-, 6- or 7-memberedheterocyclyl groups is optionally substituted with 1, 2, or 3independently selected R³⁰. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring nitrogen atom of ring A is independentlyselected from the group consisting of C₁₋₁₂ alkyl (such as C₁₋₈ alkyl,C₁₋₆ alkyl, or C₁₋₄ alkyl); C₁₋₁₂ alkyl (such as C₁₋₈ alkyl, C₁₋₆ alkyl,or C₁₋₄ alkyl) substituted with 1 substituent selected from the groupconsisting of —OH, —O(C₁₋₃ alkyl), and —NH_(2-z)(CH₃)_(z); C₁₋₄ alkylsubstituted with 1, 2, or 3 halogen (preferably F), such as —CF₃,—CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; cyclopropyl; 4-morpholinyl;homomorpholinyl; 4-piperidinyl; homopiperidinyl; 4-piperazinyl;homopiperazinyl; N-methyl-piperazin-4-yl; N-methyl-homopiperazinyl; —OH;—O(C₁₋₃ alkyl); —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl);—S(O)₂(C₁₋₃ alkyl optionally substituted with —NH_(2-z)(CH₃)_(z));—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl. In one embodiment, each R⁹ when substituting ahydrogen atom bound to a ring nitrogen atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl; n-ocytl;n-dodecyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃);—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃ alkyl);—S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl), wherein z is0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl, ethyl, propyl orisopropyl. In one embodiment, each R⁹ when substituting a hydrogen atombound to a ring nitrogen atom of ring A is independently selected fromthe group consisting of methyl; ethyl; isopropyl; cyclopropyl;—(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CH₂CF₃; —CH₂CHF₂;—CH₂CH₂F; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z); —S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH;and —O(C₁₋₃ alkyl), wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl. In one embodiment, the ringnitrogen atom of ring A is unsubstituted or each R⁹ substituting ahydrogen atom bound to a ring nitrogen atom is independently selectedfrom the group consisting of C-12 alkyl (in particular methyl, n-octyl,or n-dodecyl) and —C(═O)R¹¹ (in particular —C(═O)CH₃ or—C(═O)(CH₂)₆CH₃). In one embodiment, the ring nitrogen atom of ring A isunsubstituted or is substituted with one R⁹ being methyl.

In any of the above embodiments of the spiroquinoxaline derivative offormula (II), wherein R⁹ is bound to a ring sulfur atom of ring A, eachsuch R⁹ may be independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-memberedheterocyclyl, —OR¹¹, and ═O, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In any of the above embodiments of the spiroquinoxaline derivativeof formula (II), wherein R⁹ is bound to a ring sulfur atom of ring A,each such R⁹ may be independently selected from the group consisting ofC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, 3-, 5-, 6-or 7-membered heterocyclyl, —OR¹¹, and ═O, wherein each of the C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or 6-memberedheteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-, 6- or7-membered heterocyclyl groups is optionally substituted with 1, 2, or 3independently selected R³⁰. In one embodiment, each R⁹ when bound to aring sulfur atom of ring A is independently selected from the groupconsisting of methyl, ethyl, C₃ alkyl, C₄ alkyl, —OR^(11′), and ═O,wherein R^(11′) is selected from the group consisting of —H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or6-membered aryl (e.g., phenyl), 5- or 6-membered heteroaryl, and 3- to7-membered heterocyclyl, wherein each of the methyl, ethyl, C₃ alkyl, C₄alkyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 7-membered heterocyclyl groups is optionally substituted with 1, 2,or 3 independently selected R^(30′) (R^(30′) is a 1^(st), 2^(nd), or3^(rd) level substituent as specified above (in particular one of thetypical 1^(st), 2^(nd), or 3^(rd) level substituents as specified above)and, in each case, may be selected from the group consisting of phenyl,furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, partially and completelyhydrogenated forms of the forgoing groups, morpholino, C₁₋₃ alkyl,halogen, —CF₃, —OH, —OCH₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH, and—C(═O)OCH₃, wherein z is 0, 1, or 2). In one embodiment, each R⁹ whenbound to a ring sulfur atom of ring A is independently selected from thegroup consisting of methyl; ethyl; isopropyl; benzyl; —OH; ═O; and—O(C₁₋₃ alkyl), wherein C₁₋₃ alkyl is methyl, ethyl, propyl orisopropyl. In one embodiment, the ring sulfur atom of ring A isunsubstituted or substituted with two ═O groups. In one embodiment, thering sulfur atom of ring A is unsubstituted or ring A contains onesulfur atom which is substituted with two ═O groups (i.e., ring Acontains the group —S(═O)₂—).

In one embodiment, the spiroquinoxaline derivative has the generalformula (III)

wherein R¹ to R⁵, ring A, E, and G are as defined above (in particularwith respect to formulas (I) and (II)) or below and L is selected fromthe group consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,—(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—, wherein each of a and b isindependently selected from an integer between 0 and 3, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2,o is 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, 1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment of the spiroquinoxaline derivative of formula(III), R¹ to R⁵, ring A, E, and G are as defined above (in particularwith respect to formulas (I) and (II)) or below and L is selected fromthe group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene,—(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b), wherein each of a and b isindependently selected from 0, 1, and 2, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2,o is 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₃ alkyl, 3-, 5-, 6- or 7-membered cycloalkyl,6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-memberedheterocyclyl, —O(C₁₋₃ alkyl), and —NHR²⁰, wherein each of the C₁₋₄alkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₃ alkyl, 3-, 5-, 6- or 7-memberedcycloalkyl, 6-membered aryl, 5- or 6-membered heteroaryl, and 3-, 5-, 6-or 7-membered heterocyclyl groups is optionally substituted with 1, 2,or 3 independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (III), R¹ to R⁵, ring A, E, and Gare as defined above (in particular with respect to formulas (I) and(II)) or below and L is selected from the group consisting of C₁₋₃alkylene, —(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b)—, wherein each of aand b is independently selected from 0 and 1, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1 or 2, n is 0, 1, or 2, ois 1 or 2, wherein if n is 0 then o is 1; Y is 0, wherein each of theC₁₋₃ alkylene, 1,1-cyclopropylene, —(CH₂)_(m)—, and —(CH₂)_(n)— groupsis optionally substituted with 1, 2, or 3 independently selected R³⁰. Inone embodiment of the spiroquinoxaline derivative of formula (III), R¹to R⁵, ring A, E, and G are as defined above (in particular with respectto formulas (I) and (II)) or below and L is selected from the groupconsisting of methylene; 1,1-ethylene; 1,2-ethylene (optionallysubstituted with one R³⁰ (such as phenyl) at position 2); trimethylene(—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 2,4-butandiyl;-1,1-cyclopropylene-; —(CH₂)-1,1-cyclopropylene;-1,1-cyclopropylene-(CH₂)—; —(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—;—(CH₂)₂O—; and —(CH₂)₃O— (such as methylene; 1,1-ethylene; 1,2-ethylene;trimethylene (—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene;and —(CH₂)₂O—, in particular, methylene). In one embodiment of thespiroquinoxaline derivative of formula (III), R¹ to R⁵, ring A, E, and Gare as defined above (in particular with respect to formulas (I) and(II)) or below and L is selected from the group consisting of methylene;1,1-ethylene; 1,2-ethylene; trimethylene (—(CH₂)₃—); 2,2-propylene(—C(CH₃)₂—); -1,1-cyclopropylene-; —(CH₂)-1,1-cyclopropylene;-1,1-cyclopropylene-(CH₂)—; —(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—;—(CH₂)₂O—; and —(CH₂)₃O— (such as methylene; 1,1-ethylene; 1,2-ethylene;trimethylene (—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene;and —(CH₂)₂O—, in particular, methylene). In one embodiment of thespiroquinoxaline derivative of formula (III), R¹ to R⁵, ring A, E, and Gare as defined above (in particular with respect to formulas (I) and(II)) or below and L is selected from the group consisting of C₁alkylene, C₂ alkylene (in particular 1,2-ethylene or 1,1-ethylene), C₃alkylene (in particular trimethylene), and C₄ alkylene (in particulartetramethylene or 2,4-butandiyl), each of which being optionallysubstituted with one R³⁰. In one embodiment of the spiroquinoxalinederivative of formula (III), R¹ to R⁵, ring A, E, and G are as definedabove (in particular with respect to formulas (I) and (II)) or below andL is selected from the group consisting of methylene, 1,1-ethylene,1,2-ethylene, trimethylene, tetramethylene, 2,4-butandiyl, and2-phenyl-1,2-ethylene (—CH₂—CH(C₆H₅)—). In one embodiment of thespiroquinoxaline derivative of formula (III), R¹ to R⁵, ring A, E, and Gare as defined above (in particular with respect to formulas (I) and(II)) or below and L is selected from the group consisting of methyleneand 2-phenyl-1,2-ethylene (—CH₂—CH(C₆H₅)—).

In one embodiment, the spiroquinoxaline derivative has the generalformula (IV)

wherein R¹ to R⁵, ring A, E, and L are as defined above (in particularwith respect to formulas (I), (II) and (III)) or below and G is phenylwhich is either unsubstituted or substituted with 1, 2, 3, 4 or 5 (suchas between 1 to 4, or 1 to 3, or 1 or 2) independently selected R⁸. Inany of the above embodiments (including those of formulas (I) to (III)),wherein G is substituted, R⁸ may be, in each case, selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (IV), R¹ to R⁵, ring A, E, and Lare as defined above (in particular with respect to formulas (I), (II)and (III)) or below and R⁸ is, in each case, selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl,5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, 3-,5-, 6- or 7-membered heterocyclyl, halogen, —CN, —OR¹¹, —N(R¹²)(R¹³),—S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)SR¹¹,—C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹, —OC(═S)R¹¹,—N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein eachof the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-,6- or 7-membered heterocyclyl groups is optionally substituted with 1,2, or 3 independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (IV), R¹ to R⁵, ring A, E, and Lare as defined above (in particular with respect to formulas (I), (II)and (III)) or below and R⁸ is, in each case, selected from the groupconsisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituentselected from the group consisting of —OH, —O(C₁₋₃ alkyl), and—NH_(2-z)(CH₃)_(z); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl;cyclopropyl; 5-membered heterocyclyl (such as pyrrolidinyl);4-morpholinyl; homomorpholinyl; 4-piperidinyl; homopiperidinyl;4-piperazinyl; homopiperazinyl; N-methyl-piperazin-4-yl;N-methyl-homopiperazinyl; halogen; —CN; —OH; —O(C₁₋₃ alkyl); —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; —O-phenyl; —NH₂; —NH(C₁₋₃alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl); —S(O)₂(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z);—NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and—N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2and C₁₋₃ alkyl is methyl, ethyl, propyl or isopropyl and each of thephenyl, cyclopropyl, 5-membered heterocyclyl (such as pyrrolidinyl),4-morpholinyl, homomorpholinyl, 4-piperidinyl, homopiperidinyl,4-piperazinyl, homopiperazinyl, N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, and —O-phenyl groups is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃, —OH, —OCH₃, —SCH₃,—NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, wherein z is 0, 1, or 2.In one embodiment, each R⁸ is independently selected from the groupconsisting of methyl; ethyl; isopropyl; tert-butyl; phenyl; cyclopropyl;pyrrolidinyl (such as 4-pyrrolidinyl); —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F;halogen (in particular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl);—N(C₁₋₃ alkyl)₂; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH;—C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃alkyl); —S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and—O(C₁₋₃ alkyl), wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkylis methyl, ethyl, propyl or isopropyl. In one embodiment, each R⁸ isindependently selected from the group consisting of methyl; ethyl;isopropyl; phenyl; cyclopropyl; pyrrolidinyl (such as 4-pyrrolidinyl);—(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br); —CN;—NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (IV), R¹ to R⁵, ring A, E, and L are as definedabove (in particular with respect to formulas (I), (II) and (III)) orbelow and G is either unsubstituted or substituted with 1, 2, or 3 R⁸,wherein R⁸ is, in each case, selected from the group consisting of C₁₋₄alkyl (in particular methyl or tert-butyl); halogen (in particular F orCl); —OR¹¹ (in particular —OCH₃); and C₁₋₄ alkyl substituted with 1, 2,or 3 independently selected R³⁰ (in particular —CF₃). In one embodimentof the spiroquinoxaline derivative of formula (IV), R¹ to R⁵, ring A, E,and L are as defined above (in particular with respect to formulas (I),(II) and (III)) or below and G is either unsubstituted or substitutedwith 1 or 2 R⁸ each independently selected from the group consisting ofmethyl, F, Cl, —OCH₃, and —CF₃. In one embodiment of thespiroquinoxaline derivative of formula (IV), R¹ to R⁵, ring A, E, and Lare as defined above (in particular with respect to formulas (I), (II)and (III)) or below and G is selected from the group consisting ofunsubstituted phenyl, fluorophenyl (in particular 3-fluorophenyl),chlorophenyl (in particular 2-, 3- or 4-chlorophenyl), methylphenyl (inparticular 2- or 3-methylphenyl), tert-butylphenyl (in particular4-tert-butylphenyl), methoxyphenyl (in particular 3-methoxyphenyl),(trifluoromethyl)phenyl (in particular 3- or 4-(trifluoromethyl)phenyl),difluorophenyl (in particular 2,4- or 2,6-difluorophenyl),dichlorophenyl (in particular 2,4- or 3,4-dichlorophenyl),chlorofluorophenyl (in particular 4-chloro-2-fluorophenyl), anddimethylphenyl (in particular 3,5-dimetylphenyl). In one embodiment ofthe spiroquinoxaline derivative of formula (IV), R¹ to R⁵, ring A, E,and L are as defined above (in particular with respect to formulas (I),(II) and (III)) or below and G is selected from the group consisting ofunsubstituted phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-methylphenyl, 3-(trifluoromethyl)phenyl, 2,6-difluorophenyl,3,4-dichlorophenyl, 4-chloro-2-fluorophenyl, and 3,5-dimetylphenyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (V)

wherein R¹, ring A, E, L and G are as defined above (in particular withrespect to formulas (I), (II), (III) and (IV)) or below and each of R²,R³, R⁴, and R⁵ is H. In one embodiment of the spiroquinoxalinederivative of formula (V), R¹, ring A, E, L and G are as defined above(in particular with respect to formulas (I), (II), (III) and (IV)) orbelow and at least one of R², R³, R⁴, and R⁵ is different from H. Forexample, in one embodiment R² is different from H and each of R³, R⁴,and R⁵ is H; or R³ is different from H and each of R², R⁴, and R⁵ is H;or R⁴ is different from H and each of R², R³, and R⁵ is H; or R⁵ isdifferent from H and each of R², R³, and R⁴ is H; or both of R² and R³are different from H and both of R⁴ and R⁵ are H; or both of R² and R⁴are different from H and both of R³ and R⁵ are H; or both of R² and R⁵are different from H (preferably in this embodiment R² and R⁵ are thesame) and both of R³ and R⁴ are H; or both of R³ and R⁴ are differentfrom H (preferably in this embodiment R³ and R⁴ are the same) and bothof R² and R⁵ are H; or each of R², R³, and R⁴ is different from H and R⁵is H; or each of R², R³, and R⁵ is different from H and R⁴ is H; or eachof R², R⁴, and R⁵ is different from H and R³ is H; or each of R³, R⁴,and R⁵ is different from H and R² is H; or each of R², R³, R⁴, and R⁵ isdifferent from H. In any of the above embodiments, it is preferred thatR² and R⁵ are the same and/or R³ and R⁴ are the same.

In any of the above embodiments (in particular with respect to formulas(I), (II), (III), (IV), and (V)), each of R² to R⁵, if it does not jointogether with another of R² to R⁵ to form a ring, is independentlyselected from the group consisting of —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to7-membered cycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN,—OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment, each of R², R³, R⁴, and R⁵, if it does not jointogether with another of R² to R⁵ to form a ring, may be independentlyselected from the group consisting of —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or7-membered cycloalkyl, 3-, 5-, 6- or 7-membered heterocyclyl, halogen,—CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹,—OC(═S)R¹¹, —N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹),wherein each of the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,and 3-, 5-, 6- or 7-membered heterocyclyl groups is optionallysubstituted with 1, 2, or 3 independently selected R³⁰. In oneembodiment of the spiroquinoxaline derivative of formula (V), R¹, ringA, E, L and G are as defined above (in particular with respect toformulas (I), (II), (III), and (IV)) or below and each of R², R³, R⁴,and R⁵, if it does not join together with another of R² to R⁵ to form aring, is independently selected from the group consisting of H; C₁₋₄alkyl; C₁₋₄ alkyl substituted with 1 substituent selected from the groupconsisting of —OH, —O(C₁₋₃ alkyl), and —NH_(2-z)(CH₃)_(z); C₁₋₄ alkylsubstituted with 1, 2, or 3 halogen (preferably F), such as —CF₃,—CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl; cyclopropyl; 5-memberedheterocyclyl; 4-morpholinyl; homomorpholinyl; 4-piperidinyl;homopiperidinyl; 4-piperazinyl; homopiperazinyl;N-methyl-piperazin-4-yl; N-methyl-homopiperazinyl; halogen; —CN; —OH;—O(C₁₋₃ alkyl); —O(C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F)), such as —OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F;—O-phenyl; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl);—S(O)₂(C₁₋₃ alkyl optionally substituted with —NH_(2-z)(CH₃)_(z));—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl and each of the phenyl, cyclopropyl, 5-memberedheterocyclyl, 4-morpholinyl, homomorpholinyl, 4-piperidinyl,homopiperidinyl, 4-piperazinyl, homopiperazinyl,N-methyl-piperazin-4-yl, N-methyl-homopiperazinyl, and —O-phenyl groupsis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃,—OH, —OCH₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, whereinz is 0, 1, or 2. In one embodiment, each of R², R³, R⁴, and R⁵, if itdoes not join together with another of R² to R⁵ to form a ring, isindependently selected from the group consisting of H; methyl; ethyl;isopropyl; phenyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (inparticular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH, and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (V), R¹, ring A, E, L and G are as defined above(in particular with respect to formulas (I), (II), (III), and (IV)) orbelow and R², R³, R⁴, and R⁵ are independently selected from the groupconsisting of —H, C₁₋₄ alkyl, and halogen, wherein the C₁₋₄ alkyl isoptionally substituted with 1, 2, or 3 independently selected R³⁰ (inparticular wherein R² and R⁵ are each —H). In one embodiment of thespiroquinoxaline derivative of formula (V), R¹, ring A, E, L and G areas defined above (in particular with respect to formulas (I), (II),(III), and (IV)) or below and R², R³, R⁴, and R⁵ are independentlyselected from the group consisting of —H, methyl, F, Cl, and CF₃ (inparticular wherein R² and R⁵ are each —H). In one embodiment of thespiroquinoxaline derivative of formula (V), R¹, ring A, E, L and G areas defined above (in particular with respect to formulas (I), (II),(III), and (IV)) or below and R² and R⁵ are each —H; R³ is selected fromthe group consisting of —H, methyl, F, and Cl; and R⁴ is selected fromthe group consisting of —H, methyl, F, and Cl. In one embodiment of thespiroquinoxaline derivative of formula (V), R¹, ring A, E, L and G areas defined above (in particular with respect to formulas (I), (II),(III), and (IV)) or below and (i) R² to R⁵ are each —H; or (ii) R² andR⁵ are each —H, and both of R³ and R⁴ are F, Cl, or methyl.

In any of the above embodiments, wherein a ring is formed by (i) R² andR³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵, said ring preferably is a 3-to 7-membered ring (e.g., a ring having 5 or 6 members) which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰. The ring may be an aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N(R⁴⁰), wherein R⁴⁰ is selectedfrom the group consisting of R¹¹, —OR¹¹, —NH_(y)R²⁰ _(2-y), and—S(O)₁₋₂R¹¹, wherein R¹¹, R²⁰, and y are as defined above. In oneembodiment, the ring formed by (i) R² and R³, (ii) R³ and R⁴, and/or(iii) R⁴ and R⁵ is a 5- or 6-membered aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N, wherein at least oneheteroatom is N. In one embodiment, the ring formed by (i) R² and R³,(ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is selected from the groupconsisting of cyclopentadiene, furan, pyrrole, thiophene, imidazole,pyrazole, oxazole, isoxazole, thiazole, dioxole (e.g., 1,3-dioxole),benzene, pyridine, pyrazine, pyrimidine, pyridazine, dioxine (e.g.,1,4-dioxine), 1,2,3-triazine, 1,2,4-triazine, and di- or tetrahydroforms of each of the foregoing. In one embodiment, the ring formed by(i) R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is selected fromthe group consisting of cyclopentadiene, furan, pyrrole, thiophene,imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine,pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, anddi- or tetrahydro forms of each of the foregoing. In one embodiment, thering formed (i) R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ iscyclopentene (such as 2,3-dihydrocyclopentadiene), dioxole (such as1,3-dioxole, optionally substituted at position 2 with one or twohalogen atoms (such as F)), or dioxine (such as2,3-dihydro-[1,4]-dioxine). In one embodiment, the total number of ringsformed by (i) R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is 0or 1. Thus, in the embodiment, wherein the total number of rings formedby (i) R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is 1, only twoadjacent substituents (i.e., either (i) R² and R³, (ii) R³ and R⁴, or(iii) R⁴ and R⁵) join together with the atoms to which they are attachedto form a ring, wherein the ring is as defined in any of the aboveembodiments and the remaining of R² to R⁵ are selected from theparticular groups of moieties specified above for the situation thatthey do not join together to form a ring. For example, the remaining R²to R⁵ which do not join together to form a ring may be selected from —H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-memberedheterocyclyl, halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³),—C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In an alternative embodiment, R² to R⁵ do not join together to forma ring.

In any of the above embodiments, R² and R⁵ may be the same and/or R³ andR⁴ may be the same.

In one embodiment of the spiroquinoxaline derivative of formula (V), R¹,ring A, E, L and G are as defined above (in particular with respect toformulas (I), (II), (III), and (IV)) or below and R², R³, R⁴, and R⁵ areindependently selected from the group consisting of —H, C₁₋₄ alkyl, andhalogen, wherein the C₁₋₄ alkyl is optionally substituted with 1, 2, or3 independently selected R³⁰ (in particular wherein R² and R⁵ are each—H), or R³ and R⁴ may join together with the atoms to which they areattached to form a 5- or 6-membered ring which is optionally substitutedwith one or two independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (V), R¹, ring A, E, L and G areas defined above (in particular with respect to formulas (I), (II),(III), and (IV)) or below and R², R³, R⁴, and R⁵ are independentlyselected from the group consisting of —H, methyl, F, Cl, and CF₃ (inparticular wherein R² and R⁵ are each —H), or R³ and R⁴ may jointogether with the atoms to which they are attached to form a dioxole ordioxine ring which is optionally substituted with one or twoindependently selected halogens (in particular F). In one embodiment ofthe spiroquinoxaline derivative of formula (V), R¹, ring A, E, L and Gare as defined above (in particular with respect to formulas (I), (II),(III), and (IV)) or below and R² and R⁵ are each —H; R³ is selected fromthe group consisting of —H, methyl, F, and Cl; and R⁴ is selected fromthe group consisting of —H, methyl, F, and Cl; or R³ and R⁴ may jointogether with the atoms to which they are attached to form a dioxole (inparticular 1,3-dioxole) or dioxine (in particular2,3-dihydro-[1,4]-dioxine) ring, wherein the dioxole ring is optionallysubstituted with two F. In one embodiment of the spiroquinoxalinederivative of formula (V), R¹, ring A, E, L and G are as defined above(in particular with respect to formulas (I), (II), (III), and (IV)) orbelow and (i) R² to R⁵ are each —H; (ii) R² and R⁵ are each —H, and bothof R³ and R⁴ are F, Cl, or methyl, or (iii) R² and R⁵ are each —H, andR³ and R⁴ join together with the atoms to which they are attached toform a 2,2-difluoro-1,3-dioxole ring or a 2,3-dihydro-[1,4]-dioxinering.

In any of the above embodiments (in particular with respect to formulas(I), (II), (III), (IV), and (V)), R³⁰, in each case, may be a typical1^(st), 2^(nd), or 3^(rd) level substituent as specified above and maybe independently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 5- or 6-membered cycloalkyl, 5-, 6-, or 7-memberedheterocyclyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃ alkyl),—S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH, —C(═O)O(C₁₋₃ alkyl),—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃ alkyl),—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl, such as 4-morpholinyl, homomorpholinyl,4-piperidinyl, homopiperidinyl (i.e., azepanyl, in particular4-azepanyl), 4-piperazinyl, homopiperazinyl (i.e., diazepanyl, inparticular 2,4-diazepanyl), N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, —CH₂CH₂OCH₃, —OCH₂CH₂OCH₃,—CH₂CH₂NH_(2-z)(CH₃)_(z), —OCH₂CH₂NH_(2-z)(CH₃)_(z), —CF₃, —OCF₃.Alternatively, R³⁰ may be selected from the group consisting of phenyl,furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, partially and completelyhydrogenated forms of the forgoing groups, morpholino, C₁₋₃ alkyl,halogen, —CF₃, —OH, —OCH₃, —OCF₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH,and —C(═O)OCH₃, wherein z is 0, 1, or 2.

In one embodiment, the spiroquinoxaline derivative has the generalformula (N-I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof, whereinE is —N(R⁶)—;L is selected from the group consisting of C₁₋₁₀ alkylene, C₂₋₁₀alkenylene, C₂₋₁₀ alkynylene, 1,1-(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—,wherein each of a and b is independently selected from an integerbetween 0 and 3, and —(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is aninteger between 1 and 6, n is an integer between 0 and 3, o is aninteger between 1 and 3, wherein if n is 0 then o is 1; Y isindependently selected from O, S, and —N(R⁷)—; and each of the C₁₋₁₀alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, and —(CH₂)_(n)— groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, or —(CH₂)_(n)— group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;G is phenyl, optionally substituted with 1, 2, 3, 4 or 5 independentlyselected R⁸;ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene,optionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹;R¹ is H;R², R³, R⁴, and R⁵ are independently selected from the group consistingof —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³),—N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰;or R² and R³ may join together with the atoms to which they are attachedto form a ring which is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the ring, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1to 3, or 1 or 2) independently selected R³⁰; R³ and R⁴ may join togetherwith the atoms to which they are attached to form a ring which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰; and/or R⁴ and R⁵ may join together with theatoms to which they are attached to form a ring which is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁶ is H;R⁷ is selected from the group consisting of —H, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R⁸ is, in each case, selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen,—CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹,—S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁹ is, when substituting a hydrogen atom bound to a ring carbon atom,independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN,azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹,—OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹,—C(═X)XR¹¹, —XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groupsis optionally substituted with one or more (such as 1 to the maximumnumber of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰, and/or any two R⁹ which are bound to thesame carbon atom of ring A may join together to form ═X; or R⁹ is, whensubstituting a hydrogen atom bound to a ring nitrogen atom,independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, —OR¹¹,—N(R¹²)(R¹³), —S(O)₁₋₂R¹¹, —S(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —N¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹,—C(═X)XR¹¹, —N(R¹⁴)C(═X)R¹¹, and —N(R¹⁴)C(═X)XR¹¹, wherein each of thealkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclylgroups is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R³⁰;X is independently selected from O, S, and N(R¹⁴);R¹¹ is, in each case, selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹² and R¹³ are, in each case, independently selected from the groupconsisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl, or R² and R¹³ may join together with the nitrogen atomto which they are attached to form the group —N═CR¹⁵R¹⁶, wherein each ofthe alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R¹⁴ is independently selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR¹¹,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹⁵ and R¹⁶ are independently selected from the group consisting of —H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and—NH_(y)R²⁰ _(2-y), or R¹⁵ and R¹⁶ may join together with the atom towhich they are attached to form a ring which is optionally substitutedwith one or more (such as 1 to the maximum number of hydrogen atomsbound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;y is an integer from 0 to 2;R²⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclylgroups is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R³⁰; and R³⁰ is a 1^(st) levelsubstituent and is, in each case, independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR⁷¹, —N(R⁷²)(R⁷³),—S(O)₀₋₂R⁷¹, —S(O)₁₋₂OR⁷¹, —OS(O)₁₋₂R⁷¹, —OS(O)₁₋₂OR⁷¹,—S(O)₁₋₂N(R⁷²)(R⁷³), —OS(O)₁₋₂N(R⁷²)(R⁷³), —N(R⁷¹)S(O)₁₋₂R⁷¹,—NR⁷¹S(O)₁₋₂OR⁷¹, —NR⁷¹S(O)₁₋₂N(R⁷²)(R⁷³), —C(═X¹)R⁷¹, —C(═X¹)X¹R⁷¹,—X¹C(═X¹)R⁷, and —X¹C(═X)X¹R⁷, and/or any two R³⁰ which are bound to thesame carbon atom of a cycloalkyl or heterocyclyl group may join togetherto form ═X¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups being a 1^(st) levelsubstituent is optionally substituted by one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, or heterocyclyl group being a 1^(st) levelsubstituent, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) 2^(nd) level substituents,wherein said 2^(nd) level substituent is, in each case, independentlyselected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF₃,—CN, azido, —NO₂, —OR⁸¹, —N(R⁸²)(R⁸³), —S(O)₀₋₂R⁸¹, —S(O)₁₋₂OR⁸¹,—OS(O)₁₋₂R⁸¹, —OS(O)₁₋₂OR⁸¹, —S(O)₁₋₂N(R⁸²)(R⁸³), —OS(O)₁₋₂N(R²)(R⁸³),—N(R⁸¹)S(O)₁₋₂R⁸¹, —NR⁸¹S(O)₁₋₂OR⁸¹, —NR⁸¹S(O)₁₋₂N(R⁸²)(R⁸³),—C(═X²)R⁸¹, —C(═X²)X²R⁸¹, —X²C(═X²)R⁸¹, and —X²C(═X²)X²R⁸¹, and/or anytwo 2^(nd) level substituents which are bound to the same carbon atom ofa cycloalkyl or heterocyclyl group being a 1^(st) level substituent mayjoin together to form ═X², wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3-to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl groupsbeing a 2^(nd) level substituent is optionally substituted with one ormore (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to14-membered heteroaryl, 3- to 14-membered cycloalkyl, or 3- to14-membered heterocyclyl group being a 2^(nd) level substituent, e.g.,1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4,or 1 to 3, or 1 or 2) 3^(rd) level substituents, wherein said 3^(rd)level substituent is, in each case, independently selected from thegroup consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH,—O(C₁₋₃ alkyl), —OCF₃, —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3^(rd) levelsubstituents which are bound to the same carbon atom of a 3- to14-membered cycloalkyl or heterocyclyl group being a 2^(nd) levelsubstituent may join together to form ═O, ═S, ═NH, or ═N(C₁₋₃ alkyl);whereinR⁷¹, R⁷², and R⁷³ are independently selected from the group consistingof —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 7-membered heterocyclyl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl;R⁸¹, R⁸², and R⁸³ are independently selected from the group consistingof —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3- to 6-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 6-membered heterocyclyl, wherein each of the C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl; andX¹ and X² are independently selected from O, S, and N(R⁸⁴), wherein R⁸⁴is —H or C₁₋₃ alkyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (N-II)

wherein R¹ to R⁵, E, L and G are as defined above or below and theoptionally substituted monocyclic 4- to 10-memberedN-heterocycloalkylene ring A contains 1 ring nitrogen atom and is 4- to8-membered (preferably 5-, 6- or 7-membered, more preferably 6- or7-membered) or said ring A contains 2 or 3 ring nitrogen atoms and is 5-to 8-membered, preferably 5-, 6- or 7-membered, more preferably 6- or7-membered. In one embodiment of the spiroquinoxaline derivative offormula (N-II), ring A as such is unsaturated (i.e., the 4 to 10 membersof ring A constitute 1, 2, or 3 (preferably 1 or 2, most preferably 1)double bonds within the ring) but is not aromatic. In an alternativeembodiment of the spiroquinoxaline derivative of formula (N-II), ring Ais saturated (i.e., ring A as such is free of unsaturation within thering); however, if ring A is substituted by one or more (such as 1 tothe maximum number of hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) R⁹, R⁹ may be unsaturated (i.e., may contain double and/ortriple bonds and/or one or more (e.g., 1, 2. or 3) aromatic ring(s)). Inany of the above embodiments of the spiroquinoxaline derivative offormula (N-II), the ring nitrogen atoms of ring A (preferably all ringheteroatoms of ring A) are not at position alpha to the spiro carbonatom (i.e., in this embodiment, preferably the two atoms of ring Apositioned alpha to the spiro carbon atom are carbon atoms). In any ofthe above embodiments of the spiroquinoxaline derivative of formula(N-II), ring A may be selected from the group consisting ofpiperidinylene, azepanylene (e.g., homopiperidinylene), azetidinylene,pyrrolidinylene, azocanylene, pyrazolidinylene, hexahydropyridazinylene,hexahydropyrimidinylene, diazepanylene (e.g., homopiperazinylene),diazocanylene, triazepanylene, triazocanylene and their regioisomers,each of which is optionally substituted with one or more (such as 1 tothe maximum number of hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R⁹. In one embodiment of thespiroquinoxaline derivative of formula (N-II), ring A is selected fromthe group consisting of 3- and 4-piperidinylene (N at position 3 or 4relative to the spiro carbon atom); 3- and 4-azepanylene,3-azetidinylene, 3-pyrrolidinylene, 3-, 4-, and 5-azocanylene,3,4-pyrazolidinylene, 3,4-hexahydropyridazinylene,3,5-hexahydropyrimidinylene, 3,4-, 3,5-, 3,6-, and 4,5-diazepanylene,3,4-, 3,5-, 3,6-, 3,7-, 4,5-, and 4,6-diazocanylene, each of which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹. In one embodiment of the spiroquinoxalinederivative of formula (N-II), ring A is selected from the groupconsisting of 4-piperidinylene, 3-piperidinylene, 3-azetidinylene,3-pyrrolidinylene, 4-azepanylene, 3-azepanylene, 5-azocanylene,4-azocanylene, 3-azocanylene, and 3,6-diazepanylene (such as4-piperidinylene, 3-piperidinylene, 4-azepanylene, and 3-azepanylene),each of which is optionally substituted with one or more (such as 1 tothe maximum number of hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R⁹.

In any of the above embodiments of the spiroquinoxaline derivative offormula (N-II), ring A may be unsubstituted.

In any of the above embodiments of the spiroquinoxaline derivative offormula (N-II), wherein ring A is substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to ring A, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1to 3, or 1 or 2) independently selected R⁹, either (i) only one or more(preferably, 1, 2, or 3) ring nitrogen atoms of ring A are substitutedwith independently selected R⁹, or (ii) only one or more (preferably, 1,2, or 3) ring carbon atoms of ring A are substituted with independentlyselected R⁹, or (iii) one or more (preferably, 1, 2, or 3) ring nitrogenatoms and one or more (preferably, 1, 2, or 3) ring carbon atoms of ringA (e.g., 1 or 2 ring nitrogen atoms and 1 or 2 ring carbon atoms) aresubstituted with independently selected R⁹. For example, if ring Acontains 1 ring nitrogen atom, ring A may be substituted (i) only at thering nitrogen atom with R⁹ (preferably, the ring nitrogen atom is atposition 3 if ring A is 4- or 5-membered; at position 3 or 4 (preferably4) if ring A is 6- or 7-membered; or at position 3, 4, or 5 (preferably4 or 5) if ring A is 8-membered); (ii) only at 1 or 2 ring carbon atomsof ring A each with 1 or 2 independently selected R⁹; or (iii) at thering nitrogen atom with R⁹ (preferably, the ring nitrogen atom is atposition 3 if ring A is 4- or 5-membered; at position 3 or 4 (preferably4) if ring A is 6- or 7-membered; or at position 3, 4, or 5 (preferably4 or 5) if ring A is 8-membered) and at 1 or 2 ring carbon atoms of ringA each with 1 or 2 independently selected R⁹.

In any of the above embodiments of the spiroquinoxaline derivative offormula (N-II), wherein R⁹ substitutes a hydrogen atom bound to a ringcarbon atom of ring A, each such R⁹ may be independently selected fromthe group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰, and/or any two R⁹ which are bound tothe same carbon atom of ring A may join together to form ═X. In any ofthe above embodiments of the spiroquinoxaline derivative of formula(N-II), wherein R⁹ substitutes a hydrogen atom bound to a ring carbonatom of ring A, each such R⁹ may be independently selected from thegroup consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,3-, 5-, 6- or 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)SR¹¹,—C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹, —OC(═S)R¹¹,—N(R¹⁴)C(═O)N(R¹⁴)(R¹¹), and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein eachof the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-,6- or 7-membered heterocyclyl groups is optionally substituted with 1,2, or 3 independently selected R³⁰, and/or any two R⁹ which are bound tothe same carbon atom of ring A may join together to form ═O or ═S. Inone embodiment, each R⁹ when substituting a hydrogen atom bound to aring carbon atom of ring A is independently selected from the groupconsisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituentselected from the group consisting of —OH, —O(C₁₋₃ alkyl),—NH_(2-z)(CH₃)_(z), morpholinyl (e.g., 4-morpholinyl), piperazinyl(e.g., 1-piperazinyl), and N-methylpiperazinyl (e.g.,4-methylpiperazin-1-yl); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; cyclopropyl; 4-morpholinyl;homomorpholinyl; 4-piperidinyl; homopiperidinyl; 4-piperazinyl;homopiperazinyl; 4-methyl-piperazin-1-yl; N-methyl-homopiperazinyl;halogen; —CN; —OH; ═O; —O(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃alkyl); —S(O)₂(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl. In one embodiment, each R⁹ when substituting ahydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;tert-butyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—O(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —CH₂CF₃;—CH₂CHF₂; —CH₂CH₂F; —(CH₂)_(d)-(4-morpholinyl);—(CH₂)_(d)-(1-piperazinyl); —(CH₂)_(d)-(4-methylpiperazin-1-yl);4-morpholinyl; 4-piperazinyl; 4-methyl-piperazin-1-yl; halogen (inparticular, —F, —Cl, —Br); —NHC(═O)(C₁₋₃ alkyl optionally substitutedwith —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;halogen (in particular, —F, —Cl, —Br); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br);—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z);—S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃alkyl), wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl ismethyl, ethyl, propyl or isopropyl. In one embodiment, the ring carbonatoms of ring A are unsubstituted or each R⁹ substituting a hydrogenatom bound to a ring carbon atom is independently selected from thegroup consisting of C₁₋₄ alkyl (in particular methyl), —N(R¹²)(R¹³) (inparticular NH₂), and —N(R¹⁴)C(═O)R¹¹ (in particular NHC(O)CH₃). In oneembodiment, the ring carbon atoms of ring A are unsubstituted or onering carbon atom of ring A is substituted with one R⁹ being NH₂ or CH₃,or with two R⁹ being CH₃.

In any of the above embodiments of the spiroquinoxaline derivative offormula (N-II), wherein R⁹ substitutes a hydrogen atom bound to a ringnitrogen atom of ring A, each such R⁹ may be independently selected fromthe group consisting of C₁₋₁₂ alkyl (such as C_(8-s) alkyl or C₁₋₆alkyl), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-memberedheterocyclyl, —OR¹¹, —N(R¹²)(R¹³), —S(O)₁₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—N(R¹⁴)C(═X)R¹¹, and —N(R¹⁴)C(═X)XR¹¹, wherein each of the C₁₋₁₂ alkyl(such as C₁₋₈ alkyl or C₁₋₆ alkyl), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₁₂ alkyl (such as C₁₋₈ alkyl or C₁₋₆alkyl), C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In any of the above embodiments of the spiroquinoxaline derivativeof formula (N-II), wherein R⁹ substitutes a hydrogen atom bound to aring nitrogen atom of ring A, each such R⁹ may be independently selectedfrom the group consisting of C₁₋₁₂ alkyl (such as C_(1-s) alkyl, C₁₋₆alkyl or C₁₋₄ alkyl), C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, 3-, 5-, 6-or 7-membered heterocyclyl, —OR¹¹, —N(R¹²)(R¹³), —S(O)₁₋₂R¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹,—N(R¹⁴)C(═O)R¹¹, —N(R¹⁴)C(═O)N(R¹⁴)(R¹¹), and—N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein each of the C₁₋₁₂ alkyl (such asC_(1-s) alkyl, C₁₋₆ alkyl or C₁₋₄ alkyl), C₂₋₄ alkenyl, C₂₋₄ alkynyl,6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-memberedcycloalkyl, and 3-, 5-, 6- or 7-membered heterocyclyl groups isoptionally substituted with 1, 2, or 3 independently selected R³⁰. Inone embodiment, each R⁹ when substituting a hydrogen atom bound to aring nitrogen atom of ring A is independently selected from the groupconsisting of C₁₋₁₂ alkyl (such as C₁₋₈ alkyl, C₁₋₆ alkyl or C₁₋₄alkyl); C₁₋₁₂ alkyl (such as C_(1-s) alkyl, C₁₋₆ alkyl or C₁₋₄ alkyl)substituted with 1 substituent selected from the group consisting of—OH, —O(C₁₋₃ alkyl), and —NH_(2-z)(CH₃)_(z); C₁₋₄ alkyl substituted with1, 2, or 3 halogen (preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or—CH₂CH₂F; cyclopropyl; 4-morpholinyl; homomorpholinyl; 4-piperidinyl;homopiperidinyl; 4-piperazinyl; homopiperazinyl;N-methyl-piperazin-4-yl; N-methyl-homopiperazinyl; —OH; —O(C₁₋₃ alkyl);—NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl optionally substituted with —NH_(2-z)(CH₃)_(z));—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl. In one embodiment, each R⁹ when substituting ahydrogen atom bound to a ring nitrogen atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl; n-ocytl;n-dodecyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃);—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃ alkyl);—S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl), wherein z is0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl, ethyl, propyl orisopropyl. In one embodiment, each R⁹ when substituting a hydrogen atombound to a ring nitrogen atom of ring A is independently selected fromthe group consisting of methyl; ethyl; isopropyl; cyclopropyl;—(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CH₂CF₃; —CH₂CHF₂;—CH₂CH₂F; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z); —S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH;and —O(C₁₋₃ alkyl), wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl. In one embodiment, the ringnitrogen atom of ring A is unsubstituted or each R⁹ substituting ahydrogen atom bound to a ring nitrogen atom is independently selectedfrom the group consisting of C₁₋₁₂ alkyl (in particular methyl, n-octyl,or n-dodecyl) and —C(═O)R¹¹ (in particular —C(═O)CH₃ or—C(═O)(CH₂)₆CH₃). In one embodiment, the ring nitrogen atom of ring A isunsubstituted or is substituted with one R⁹ being methyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (N-III)

wherein R¹ to R⁵, ring A, E, and G are as defined above (in particularwith respect to formulas (N-I) and (N-II)) or below and L is selectedfrom the group consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, —(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—, wherein each of a andb is independently selected from an integer between 0 and 3, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2,o is 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, 1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment of the spiroquinoxaline derivative of formula(N-III), R¹ to R⁵, ring A, E, and G are as defined above (in particularwith respect to formulas (N-I) and (N-II)) or below and L is selectedfrom the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene, C₂₋₄alkynylene, —(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b), wherein each of aand b is independently selected from 0, 1, and 2, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2,o is 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₃ alkyl, 3-, 5-, 6- or 7-membered cycloalkyl,6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-memberedheterocyclyl, —O(C₁₋₃ alkyl), and —NHR²⁰, wherein each of the C₁₋₄alkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₃ alkyl, 3-, 5-, 6- or 7-memberedcycloalkyl, 6-membered aryl, 5- or 6-membered heteroaryl, and 3-, 5-, 6-or 7-membered heterocyclyl groups is optionally substituted with 1, 2,or 3 independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (N-III), R¹ to R⁵, ring A, E, andG are as defined above (in particular with respect to formulas (N-I) and(N-II)) or below and L is selected from the group consisting of C₁₋₃alkylene, —(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b)—, wherein each of aand b is independently selected from 0 and 1, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1 or 2, n is 0, 1, or 2, ois 1 or 2, wherein if n is 0 then o is 1; Y is 0, wherein each of theC₁₋₃ alkylene, 1,1-cyclopropylene, —(CH₂)_(m)—, and —(CH₂)_(n)— groupsis optionally substituted with 1, 2, or 3 independently selected R³⁰. Inone embodiment of the spiroquinoxaline derivative of formula (N-III), R¹to R⁵, ring A, E, and G are as defined above (in particular with respectto formulas (N-I) and (N-II)) or below and L is selected from the groupconsisting of methylene; 1,1-ethylene; 1,2-ethylene (optionallysubstituted with one R³⁰ (such as phenyl) at position 2); trimethylene(—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 2,4-butandiyl;-1,1-cyclopropylene-; —(CH₂)-1,1-cyclopropylene;-1,1-cyclopropylene-(CH₂)—; —(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—;—(CH₂)₂O—; and —(CH₂)₃O— (such as methylene; 1,1-ethylene; 1,2-ethylene;trimethylene (—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene;and —(CH₂)₂O—, in particular, methylene). In one embodiment of thespiroquinoxaline derivative of formula (N-III), R¹ to R⁵, ring A, E, andG are as defined above (in particular with respect to formulas (N-I) and(N-II)) or below and L is selected from the group consisting ofmethylene; 1,1-ethylene; 1,2-ethylene; trimethylene (—(CH₂)₃—);2,2-propylene (—C(CH₃)₂—); -1,1-cyclopropylene-;—(CH₂)-1,1-cyclopropylene; -1,1-cyclopropylene-(CH₂)—;—(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—; —(CH₂)₂O—; and —(CH₂)₃O— (suchas methylene; 1,1-ethylene; 1,2-ethylene; trimethylene (—(CH₂)₃—);2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene; and —(CH₂)₂O—, inparticular, methylene). In one embodiment of the spiroquinoxalinederivative of formula (N-III), R¹ to R⁵, ring A, E, and G are as definedabove (in particular with respect to formulas (N-I) and (N-II)) or belowand L is selected from the group consisting of C₁ alkylene, C₂ alkylene(in particular 1,2-ethylene or 1,1-ethylene), C₃ alkylene (in particulartrimethylene), and C₄ alkylene (in particular tetramethylene or2,4-butandiyl), each of which being optionally substituted with one R³⁰.In one embodiment of the spiroquinoxaline derivative of formula (N-III),R¹ to R⁵, ring A, E, and G are as defined above (in particular withrespect to formulas (N-I) and (N-II)) or below and L is selected fromthe group consisting of methylene, 1,1-ethylene, 1,2-ethylene,trimethylene, tetramethylene, 2,4-butandiyl, and 2-phenyl-1,2-ethylene(—CH₂—CH(C₆H₅)—). In one embodiment of the spiroquinoxaline derivativeof formula (N-III), R¹ to R⁵, ring A, E, and G are as defined above (inparticular with respect to formulas (N-I) and (N-II)) or below and L isselected from the group consisting of methylene and2-phenyl-1,2-ethylene (—CH₂—CH(C₆H₅)—).

In one embodiment, the spiroquinoxaline derivative has the generalformula (N-IV)

wherein R¹ to R⁵, ring A, E, and L are as defined above (in particularwith respect to formulas (N-I), (N-II) and (N-III)) or below and G isphenyl which is either unsubstituted or substituted with 1, 2, 3, 4 or 5(such as between 1 to 4, or 1 to 3, or 1 or 2) independently selectedR⁸. In any of the above embodiments (including those of formulas (N-I)to (N-III)), wherein G is substituted, R⁸ may be, in each case, selectedfrom the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (N-IV), R¹ to R⁵, ring A, E, andL are as defined above (in particular with respect to formulas (N-I),(N-II) and (N-III)) or below and R⁸ is, in each case, selected from thegroup consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,3-, 5-, 6- or 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R, —C(═O)OR¹¹, —C(═O)SR¹¹,—C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R⁴)C(═O)R¹¹, —OC(═O)R¹¹, —OC(═S)R¹¹,—N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein eachof the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-,6- or 7-membered heterocyclyl groups is optionally substituted with 1,2, or 3 independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (N-IV), R¹ to R⁵, ring A, E, andL are as defined above (in particular with respect to formulas (N-I),(N-II) and (N-III)) or below and R⁸ is, in each case, selected from thegroup consisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1substituent selected from the group consisting of —OH, —O(C₁₋₃ alkyl),and —NH_(2-z)(CH₃)_(z); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl;cyclopropyl; 5-membered heterocyclyl (such as pyrrolidinyl);4-morpholinyl; homomorpholinyl; 4-piperidinyl; homopiperidinyl;4-piperazinyl; homopiperazinyl; N-methyl-piperazin-4-yl;N-methyl-homopiperazinyl; halogen; —CN; —OH; —O(C₁₋₃ alkyl); —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; —O-phenyl; —NH₂; —NH(C₁₋₃alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl); —S(O)₂(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z);—NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and—N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2and C₁₋₃ alkyl is methyl, ethyl, propyl or isopropyl and each of thephenyl, cyclopropyl, 5-membered heterocyclyl (such as pyrrolidinyl),4-morpholinyl, homomorpholinyl, 4-piperidinyl, homopiperidinyl,4-piperazinyl, homopiperazinyl, N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, and —O-phenyl groups is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃, —OH, —OCH₃, —SCH₃,—NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, wherein z is 0, 1, or 2.In one embodiment, each R⁸ is independently selected from the groupconsisting of methyl; ethyl; isopropyl; tert-butyl; phenyl; cyclopropyl;pyrrolidinyl (such as 4-pyrrolidinyl); —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F;halogen (in particular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl);—N(C₁₋₃ alkyl)₂; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH;—C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃alkyl); —S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and—O(C₁₋₃ alkyl), wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkylis methyl, ethyl, propyl or isopropyl. In one embodiment, each R⁸ isindependently selected from the group consisting of methyl; ethyl;isopropyl; phenyl; cyclopropyl; pyrrolidinyl (such as 4-pyrrolidinyl);—(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br); —CN;—NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (N-IV), R¹ to R⁵, ring A, E, and L are as definedabove (in particular with respect to formulas (N-I), (N-II) and (N-III))or below and G is either unsubstituted or substituted with 1, 2, or 3R⁸, wherein R⁸ is, in each case, selected from the group consisting ofC₁₋₄ alkyl (in particular methyl or tert-butyl); halogen (in particularF or Cl); —OR¹¹ (in particular —OCH₃); and C₁₋₄ alkyl substituted with1, 2, or 3 independently selected R³⁰ (in particular —CF₃). In oneembodiment of the spiroquinoxaline derivative of formula (N-IV), R¹ toR⁵, ring A, E, and L are as defined above (in particular with respect toformulas (N-I), (N-II) and (N-III)) or below and G is eitherunsubstituted or substituted with 1 or 2 R⁸ each independently selectedfrom the group consisting of methyl, F, Cl, —OCH₃, and —CF₃. In oneembodiment of the spiroquinoxaline derivative of formula (N-IV), R¹ toR⁵, ring A, E, and L are as defined above (in particular with respect toformulas (N-I), (N-II) and (N-III)) or below and G is selected from thegroup consisting of unsubstituted phenyl, fluorophenyl (in particular3-fluorophenyl), chlorophenyl (in particular 2-, 3- or 4-chlorophenyl),methylphenyl (in particular 2- or 3-methylphenyl), tert-butylphenyl (inparticular 4-tert-butylphenyl), methoxyphenyl (in particular3-methoxyphenyl), (trifluoromethyl)phenyl (in particular 3- or4-(trifluoromethyl)phenyl), difluorophenyl (in particular 2,4- or2,6-difluorophenyl), dichlorophenyl (in particular 2,4- or3,4-dichlorophenyl), chlorofluorophenyl (in particular4-chloro-2-fluorophenyl), and dimethylphenyl (in particular3,5-dimetylphenyl). In one embodiment of the spiroquinoxaline derivativeof formula (N-IV), R¹ to R⁵, ring A, E, and L are as defined above (inparticular with respect to formulas (N-I), (N-II) and (N-III)) or belowand G is selected from the group consisting of unsubstituted phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl,3-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 3,4-dichlorophenyl,4-chloro-2-fluorophenyl, and 3,5-dimetylphenyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (N-V)

wherein R¹, ring A, E, L and G are as defined above (in particular withrespect to formulas (N-I), (N-II), (N-III) and (N-IV)) or below and eachof R², R³, R⁴, and R⁵ is H. In one embodiment of the spiroquinoxalinederivative of formula (N-V), R¹, ring A, E, L and G are as defined above(in particular with respect to formulas (N-I), (N-II), (N-III) and(N-IV)) or below and at least one of R², R³, R⁴, and R⁵ is differentfrom H. For example, in one embodiment R² is different from H and eachof R³, R⁴, and R⁵ is H; or R³ is different from H and each of R², R⁴,and R⁵ is H; or R⁴ is different from H and each of R², R³, and R⁵ is H;or R⁵ is different from H and each of R², R³, and R⁴ is H; or both of R²and R³ are different from H and both of R⁴ and R⁵ are H; or both of R²and R⁴ are different from H and both of R³ and R⁵ are H; or both of R²and R⁵ are different from H (preferably in this embodiment R² and R⁵ arethe same) and both of R³ and R⁴ are H; or both of R³ and R⁴ aredifferent from H (preferably in this embodiment R³ and R⁴ are the same)and both of R² and R⁵ are H; or each of R², R³, and R⁴ is different fromH and R⁵ is H; or each of R², R³, and R⁵ is different from H and R⁴ isH; or each of R², R⁴, and R⁵ is different from H and R³ is H; or each ofR³, R⁴, and R⁵ is different from H and R² is H; or each of R², R³, R⁴,and R⁵ is different from H. In any of the above embodiments, it ispreferred that R² and R⁵ are the same and/or R³ and R⁴ are the same.

In any of the above embodiments (in particular with respect to formulas(N-I), (N-II), (N-III), (N-IV), and (N-V)), each of R² to R⁵, if it doesnot join together with another of R² to R⁵ to form a ring, isindependently selected from the group consisting of —H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl,halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment, each of R², R³, R⁴, and R⁵, if it does not jointogether with another of R² to R⁵ to form a ring, may be independentlyselected from the group consisting of —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or7-membered cycloalkyl, 3-, 5-, 6- or 7-membered heterocyclyl, halogen,—CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹,—OC(═S)R¹¹, —N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹),wherein each of the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,and 3-, 5-, 6- or 7-membered heterocyclyl groups is optionallysubstituted with 1, 2, or 3 independently selected R³⁰. In oneembodiment of the spiroquinoxaline derivative of formula (N-V), R¹, ringA, E, L and G are as defined above (in particular with respect toformulas (N-I), (N-II), (N-III), and (N-IV)) or below and each of R²,R³, R⁴, and R⁵, if it does not join together with another of R² to R⁵ toform a ring, is independently selected from the group consisting of H;C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituent selected from thegroup consisting of —OH, —O(C₁₋₃ alkyl), and —NH_(2-z)(CH₃)_(z); C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F), such as —CF₃,—CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl; cyclopropyl; 5-memberedheterocyclyl; 4-morpholinyl; homomorpholinyl; 4-piperidinyl;homopiperidinyl; 4-piperazinyl; homopiperazinyl;N-methyl-piperazin-4-yl; N-methyl-homopiperazinyl; halogen; —CN; —OH;—O(C₁₋₃ alkyl); —O(C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F)), such as —OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F;—O-phenyl; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl);—S(O)₂(C₁₋₃ alkyl optionally substituted with —NH_(2-z)(CH₃)_(z));—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl and each of the phenyl, cyclopropyl, 5-memberedheterocyclyl, 4-morpholinyl, homomorpholinyl, 4-piperidinyl,homopiperidinyl, 4-piperazinyl, homopiperazinyl,N-methyl-piperazin-4-yl, N-methyl-homopiperazinyl, and —O-phenyl groupsis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃,—OH, —OCH₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, whereinz is 0, 1, or 2. In one embodiment, each of R², R³, R⁴, and R⁵, if itdoes not join together with another of R² to R⁵ to form a ring, isindependently selected from the group consisting of H; methyl; ethyl;isopropyl; phenyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (inparticular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH, and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (N-V), R¹, ring A, E, L and G are as defined above(in particular with respect to formulas (N-I), (N-II), (N-III), and(N-IV)) or below and R², R³, R⁴, and R⁵ are independently selected fromthe group consisting of —H, C₁₋₄ alkyl, and halogen, wherein the C₁₋₄alkyl is optionally substituted with 1, 2, or 3 independently selectedR³⁰ (in particular wherein R² and R⁵ are each —H). In one embodiment ofthe spiroquinoxaline derivative of formula (N-V), R¹, ring A, E, L and Gare as defined above (in particular with respect to formulas (N-I),(N-II), (N-III), and (N-IV)) or below and R², R³, R⁴, and R⁵ areindependently selected from the group consisting of —H, methyl, F, Cl,and CF₃ (in particular wherein R² and R⁵ are each —H). In one embodimentof the spiroquinoxaline derivative of formula (N-V), R¹, ring A, E, Land G are as defined above (in particular with respect to formulas(N-I), (N-II), (N-III), and (N-IV)) or below and R² and R⁵ are each —H;R³ is selected from the group consisting of —H, methyl, F, and Cl; andR⁴ is selected from the group consisting of —H, methyl, F, and Cl. Inone embodiment of the spiroquinoxaline derivative of formula (N-V), R¹,ring A, E, L and G are as defined above (in particular with respect toformulas (N-I), (N-II), (N-III), and (N-IV)) or below and (i) R² to R⁵are each —H; or (ii) R² and R⁵ are each —H, and both of R³ and R⁴ are F,Cl, or methyl.

In any of the above embodiments, wherein a ring is formed by (i) R² andR³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵, said ring preferably is a 3-to 7-membered ring (e.g., a ring having 5 or 6 members) which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰. The ring may be an aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N(R⁴⁰), wherein R⁴⁰ is selectedfrom the group consisting of R¹¹, —OR¹, —NH_(y)R²⁰ _(2-y), and—S(O)₁₋₂R¹¹, wherein R¹¹, R²⁰, and y are as defined above. In oneembodiment, the ring formed by (i) R² and R³, (ii) R³ and R⁴, and/or(iii) R⁴ and R⁵ is a 5- or 6-membered aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N, wherein at least oneheteroatom is N. In one embodiment, the ring formed by (i) R² and R³,(ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is selected from the groupconsisting of cyclopentadiene, furan, pyrrole, thiophene, imidazole,pyrazole, oxazole, isoxazole, thiazole, dioxole (e.g., 1,3-dioxole),benzene, pyridine, pyrazine, pyrimidine, pyridazine, dioxine (e.g.,1,4-dioxine), 1,2,3-triazine, 1,2,4-triazine, and di- or tetrahydroforms of each of the foregoing. In one embodiment, the ring formed (i)R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is cyclopentene (suchas 2,3-dihydrocyclopentadiene), dioxole (such as 1,3-dioxole, optionallysubstituted at position 2 with one or two halogen atoms (such as F)), ordioxine (such as 2,3-dihydro-[1,4]-dioxine). In one embodiment, thetotal number of rings formed by (i) R² and R³, (ii) R³ and R⁴, and/or(iii) R⁴ and R⁵ is 0 or 1. Thus, in the embodiment, wherein the totalnumber of rings formed by (i) R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴and R⁵ is 1, only two adjacent substituents (i.e., either (i) R² and R³,(ii) R³ and R⁴, or (iii) R⁴ and R⁵) join together with the atoms towhich they are attached to form a ring, wherein the ring is as definedin any of the above embodiments and the remaining of R² to R⁵ areselected from the particular groups of moieties specified above for thesituation that they do not join together to form a ring. For example,the remaining R² to R⁵ which do not join together to form a ring may beselected from —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰. In an alternative embodiment, R² to R⁵do not join together to form a ring.

In any of the above embodiments, R² and R⁵ may be the same and/or R³ andR⁴ may be the same.

In one embodiment of the spiroquinoxaline derivative of formula (N-V),R¹, ring A, E, L and G are as defined above (in particular with respectto formulas (N-I), (N-II), (N-III), and (N-IV)) or below and R², R³, R⁴,and R⁵ are independently selected from the group consisting of —H, C₁₋₄alkyl, and halogen, wherein the C₁₋₄ alkyl is optionally substitutedwith 1, 2, or 3 independently selected R³⁰ (in particular wherein R² andR⁵ are each —H), or R³ and R⁴ may join together with the atoms to whichthey are attached to form a 5- or 6-membered ring which is optionallysubstituted with one or two independently selected R³⁰. In oneembodiment of the spiroquinoxaline derivative of formula (N-V), R¹, ringA, E, L and G are as defined above (in particular with respect toformulas (N-I), (N-II), (N-III), and (N-IV)) or below and R², R³, R⁴,and R⁵ are independently selected from the group consisting of —H,methyl, F, Cl, and CF₃ (in particular wherein R² and R⁵ are each —H), orR³ and R⁴ may join together with the atoms to which they are attached toform a dioxole or dioxine ring which is optionally substituted with oneor two independently selected halogens (in particular F). In oneembodiment of the spiroquinoxaline derivative of formula (N-V), R¹, ringA, E, L and G are as defined above (in particular with respect toformulas (N-I), (N-II), (N-III), and (N-IV)) or below and R² and R⁵ areeach —H; R³ is selected from the group consisting of —H, methyl, F, andCl; and R⁴ is selected from the group consisting of —H, methyl, F, andCl; or R³ and R⁴ may join together with the atoms to which they areattached to form a dioxole (in particular 1,3-dioxole) or dioxine (inparticular 2,3-dihydro-[1,4]-dioxine) ring, wherein the dioxole ring isoptionally substituted with two F. In one embodiment of thespiroquinoxaline derivative of formula (N-V), R¹, ring A, E, L and G areas defined above (in particular with respect to formulas (N-I), (N-II),(N-III), and (N-IV)) or below and (i) R² to R⁵ are each —H; (ii) R² andR⁵ are each —H, and both of R³ and R⁴ are F, Cl, or methyl, or (iii) R²and R⁵ are each —H, and R³ and R⁴ join together with the atoms to whichthey are attached to form a 2,2-difluoro-1,3-dioxole ring or a2,3-dihydro-[1,4]-dioxine ring.

In any of the above embodiments (in particular with respect to formulas(N-I), (N-II), (N-III), (N-IV), and (N-V)), R³⁰, in each case, may be atypical 1^(st), 2^(nd), or 3^(rd) level substituent as specified aboveand may be independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5-, 6-, or7-membered heterocyclyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, such as 4-morpholinyl,homomorpholinyl, 4-piperidinyl, homopiperidinyl (i.e., azepanyl, inparticular 4-azepanyl), 4-piperazinyl, homopiperazinyl (i.e.,diazepanyl, in particular 2,4-diazepanyl), N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, —CH₂CH₂OCH₃, —OCH₂CH₂OCH₃,—CH₂CH₂NH_(2-z)(CH₃)_(z), —OCH₂CH₂NH_(2-z)(CH₃)_(z), —CF₃, —OCF₃.Alternatively, R³⁰ may be selected from the group consisting of phenyl,furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, partially and completelyhydrogenated forms of the forgoing groups, morpholino, C₁₋₃ alkyl,halogen, —CF₃, —OH, —OCH₃, —OCF₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH,and —C(═O)OCH₃, wherein z is 0, 1, or 2.

In one embodiment, the spiroquinoxaline derivative has the generalformula (O/S-I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof,whereinE is —N(R⁶)—;L is selected from the group consisting of C₁₋₁₀ alkylene, C₂₋₁₀alkenylene, C₂₋₁₀ alkynylene, 1,1-(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—,wherein each of a and b is independently selected from an integerbetween 0 and 3, and —(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is aninteger between 1 and 6, n is an integer between 0 and 3, o is aninteger between 1 and 3, wherein if n is 0 then o is 1; Y isindependently selected from O, S, and —N(R⁷)—; and each of the C₁₋₁₀alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, and —(CH₂)_(n)— groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, or —(CH₂)_(n)— group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;G is phenyl, optionally substituted with 1, 2, 3, 4 or 5 independentlyselected R⁸;ring A is a monocyclic 4- to 10-membered O/S-heterocycloalkylene,optionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹;R¹ is H;R², R³, R⁴, and R⁵ are independently selected from the group consistingof —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³),—N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰;or R² and R³ may join together with the atoms to which they are attachedto form a ring which is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the ring, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1to 3, or 1 or 2) independently selected R³⁰; R³ and R⁴ may join togetherwith the atoms to which they are attached to form a ring which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰; and/or R⁴ and R⁵ may join together with theatoms to which they are attached to form a ring which is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁶ is H;R⁷ is selected from the group consisting of —H, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R⁸ is, in each case, selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen,—CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹,—S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R³),—OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁹ is, when substituting a hydrogen atom bound to a ring carbon atom,independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN,azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹,—OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R²)(R³), —OS(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹,—C(═X)XR¹¹, —XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groupsis optionally substituted with one or more (such as 1 to the maximumnumber of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰, and/or any two R⁹ which are bound to thesame carbon atom of ring A may join together to form ═X; or R⁹ is, whenbound to a ring sulfur atom of ring A, independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, —OR¹¹, and ═O, wherein each of the alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groupsis optionally substituted with one or more (such as 1 to the maximumnumber of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰;X is independently selected from O, S, and N(R¹⁴);R¹¹ is, in each case, selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹² and R¹³ are, in each case, independently selected from the groupconsisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl, or R¹² and R¹³ may join together with the nitrogenatom to which they are attached to form the group —N═CR¹⁵R¹⁶, whereineach of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R¹⁴ is independently selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR¹¹,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹⁵ and R¹⁶ are independently selected from the group consisting of —H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and—NH_(y)R²⁰ _(2-y), or R¹⁵ and R¹⁶ may join together with the atom towhich they are attached to form a ring which is optionally substitutedwith one or more (such as 1 to the maximum number of hydrogen atomsbound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;y is an integer from 0 to 2;R²⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclylgroups is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R³⁰; and R³⁰ is a 1^(st) levelsubstituent and is, in each case, independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR⁷¹, —N(R⁷²)(R⁷³),—S(O)₀₋₂R⁷¹, —S(O)₁₋₂OR⁷¹, —OS(O)₁₋₂R⁷¹, —OS(O)₁₋₂OR⁷¹,—S(O)₁₋₂N(R⁷²)(R⁷³), —OS(O)₁₋₂N(R⁷²)(R⁷³), —N(R⁷¹)S(O)₁₋₂R⁷¹,—NR⁷¹S(O)₁₋₂OR⁷¹, —NR^(T1) S(O)₁₋₂N(R⁷²)(R⁷³), —C(═X¹)R⁷¹, —C(═X¹)X¹R⁷¹,—X¹C(═X¹)R⁷¹, and —X¹C(═X¹)X¹R⁷¹, and/or any two R³⁰ which are bound tothe same carbon atom of a cycloalkyl or heterocyclyl group may jointogether to form ═X¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups being a 1^(st) levelsubstituent is optionally substituted by one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, or heterocyclyl group being a 1^(st) levelsubstituent, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) 2^(nd) level substituents,wherein said 2^(nd) level substituent is, in each case, independentlyselected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF₃,—CN, azido, —NO₂, —OR⁸¹, —N(R⁸²)(R⁸³), —S(O)₀₋₂R⁸¹, —S(O)₁₋₂OR⁸¹,—OS(O)₁₋₂R⁸¹, —OS(O)₁₋₂OR⁸¹, —S(O)₁₋₂N(R⁸²)(R⁸³), —OS(O)₁₋₂N(R⁸²)(R⁸³),—N(R⁸¹)S(O)₁₋₂R⁸¹, —NR⁸¹S(O)₁₋₂OR⁸¹, —NR⁸¹S(O)₁₋₂N(R⁸²)(R⁸³),—C(═X²)R⁸¹, —C(═X²)X²R⁸¹, —X²C(═X²)R⁸¹, and —X²C(═X²)X²R⁸¹, and/or anytwo 2^(nd) level substituents which are bound to the same carbon atom ofa cycloalkyl or heterocyclyl group being a 1^(st) level substituent mayjoin together to form ═X², wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3-to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl groupsbeing a 2^(nd) level substituent is optionally substituted with one ormore (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to14-membered heteroaryl, 3- to 14-membered cycloalkyl, or 3- to14-membered heterocyclyl group being a 2^(nd) level substituent, e.g.,1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4,or 1 to 3, or 1 or 2) 3^(rd) level substituents, wherein said 3^(rd)level substituent is, in each case, independently selected from thegroup consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH,—O(C₁₋₃ alkyl), —OCF₃, —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3^(rd) levelsubstituents which are bound to the same carbon atom of a 3- to14-membered cycloalkyl or heterocyclyl group being a 2^(nd) levelsubstituent may join together to form ═O, ═S, ═NH, or ═N(C₁₋₃ alkyl);whereinR⁷¹, R⁷², and R⁷³ are independently selected from the group consistingof —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 7-membered heterocyclyl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl;R⁸¹, R⁸², and R⁸³ are independently selected from the group consistingof —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3- to 6-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 6-membered heterocyclyl, wherein each of the C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl; andX¹ and X² are independently selected from O, S, and N(R⁸⁴), wherein R⁸⁴is —H or C₁₋₃ alkyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (O/S-II)

wherein R¹ to R⁵, E, L and G are as defined above or below and theoptionally substituted monocyclic 4- to 10-memberedO/S-heterocycloalkylene ring A contains 1 ring oxygen or sulfur atom andis 4- to 8-membered (preferably 5-, 6- or 7-membered, more preferably 6-or 7-membered) or said ring A contains 2 ring heteroatoms selected fromoxygen and sulfur and is 5- to 8-membered, preferably 5-, 6- or7-membered, more preferably 6- or 7-membered. In one embodiment of thespiroquinoxaline derivative of formula (O/S-II), ring A as such isunsaturated (i.e., the 4 to 10 members of ring A constitute 1, 2, or 3(preferably 1 or 2, most preferably 1) double bonds within the ring) butis not aromatic. In an alternative embodiment of the spiroquinoxalinederivative of formula (O/S-II), ring A is saturated (i.e., ring A assuch is free of unsaturation within the ring); however, if ring A issubstituted by one or more (such as 1 to the maximum number of hydrogenatoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10,such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)R⁹, R⁹ may beunsaturated (i.e., may contain double and/or triple bonds and/or one ormore (e.g., 1, 2. or 3) aromatic ring(s)). In any of the aboveembodiments of the spiroquinoxaline derivative of formula (O/S-II), thering oxygen or sulfur atoms of ring A (preferably all ring heteroatomsof ring A) are not at position alpha to the spiro carbon atom (i.e., inthis embodiment, preferably the two atoms of ring A positioned alpha tothe spiro carbon atom are carbon atoms). In any of the above embodimentsof the spiroquinoxaline derivative of formula (O/S-II), ring A may beselected from the group consisting of di- and tetrahydropyranylene, di-and tetrahydrothiopyranylene, oxepanylene, thiepanylene, oxetanylene,thietanylene, di- and tetrahydrofuranylene, di- andtetrahydrothienylene, oxocanylene, thiocanylene, dithiolanylene,oxathiolanylene, dioxanylene, dithianylene, oxathianylene,dioxepanylene, dithiepanylene, oxathiepanylene, dioxocanylene,dithiocanylene, oxathiocanylene, and their regioisomers, each of whichis optionally substituted with one or more (such as 1 to the maximumnumber of hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹. In one embodiment of the spiroquinoxalinederivative of formula (O/S-II), ring A is selected from the groupconsisting of 3- and 4-tetrahydropyranylene (O at position 3 or 4relative to the spiro carbon atom); 3- and 4-tetrahydrothiopyranylene;3- and 4-oxepanylene; 3- and 4-thiepanylene; 3-oxetanylene;3-thietanylene; 3-tetrahydrofuranylene; 3-tetrahydrothienylene; 3-, 4-,and 5-oxocanylene; 3-, 4-, and 5-thiocanylene; 3,4-dithiolanylene;3,4-oxathiolanylene; 3,5-dioxanylene; 3,4- and 3,5-dithianylene; 3,4-,3,5-, and 4,3-oxathianylene; 3,5- and 3,6-dioxepanylene; 3,4-, 3,5-,3,6-, and 4,5-dithiepanylene; 3,4-, 3,5-, 3,6-, 4,5-, 4,3-, and4,2-oxathiepanylene; 3,5-, 3,6-, 3,7-, and 4,6-dioxocanylene; 3,3-,3,4-, 3,5-, 3,6, 3,7-, 4,5-, and 4,6-dithiocanylene; and 3,4-, 3,5-,3,6-, 3,7-, 4,5-, 4,6, 4,7-, 4-3-, 5,4-, and 5,3-oxathiocanylene, eachof which is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R⁹. In one embodiment of thespiroquinoxaline derivative of formula (O/S-II), ring A is selected fromthe group consisting of 4-tetrahydropyranylene,4-tetrahydrothiopyranylene, 3-tetrahydropyranylene,3-tetrahydrothiopyranylene, 4-oxepanylene, 4-thiepanylene,3-oxepanylene, 3-thiepanylene, 3-oxetanylene, 3-thietanylene,3-tetrahydrofuranylene, 3-tetrahydrothienylene, 5-oxocanylene,5-thiocanylene, 4-oxocanylene, and 4-thiocanylene (such as-tetrahydropyranylene, 4-tetrahydrothiopyranylene,3-tetrahydropyranylene, 3-tetrahydrothiopyranylene, 4-oxepanylene,4-thiepanylene, 3-oxepanylene, and 3-thiepanylene), each of which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹.

In any of the above embodiments of the spiroquinoxaline derivative offormula (O/S-II), ring A may be unsubstituted.

In any of the above embodiments of the spiroquinoxaline derivative offormula (O/S-II), wherein ring A is substituted with one or more (suchas 1 to the maximum number of hydrogen atoms bound to ring A, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R⁹, either (i) only one ormore (preferably, 1 or 2) ring sulfur atoms of ring A are substitutedwith independently selected R⁹, or (ii) only one or more (preferably, 1,2, or 3) ring carbon atoms of ring A are substituted with independentlyselected R⁹, or (iii) one or more (preferably, 1 or 2) ring sulfur atomsand one or more (preferably, 1, 2, or 3) ring carbon atoms of ring A(e.g., 1 or 2 ring sulfur atoms and 1 or 2 ring carbon atoms) aresubstituted with independently selected R⁹. For example, if ring Acontains 1 ring sulfur atom, ring A may be substituted (i) only at thering sulfur atom with R⁹ (preferably, the ring sulfur atom is atposition 3 if ring A is 4- or 5-membered; at position 3 or 4 (preferably4) if ring A is 6- or 7-membered; or at position 3, 4, or 5 (preferably4 or 5) if ring A is 8-membered); (ii) only at 1 or 2 ring carbon atomsof ring A each with 1 or 2 independently selected R⁹; or (iii) at thering sulfur atom with R⁹ (preferably, the ring sulfur atom is atposition 3 if ring A is 4- or 5-membered; at position 3 or 4 (preferably4) if ring A is 6- or 7-membered; or at position 3, 4, or 5 (preferably4 or 5) if ring A is 8-membered) and at 1 or 2 ring carbon atoms of ringA each with 1 or 2 independently selected R⁹.

In any of the above embodiments of the spiroquinoxaline derivative offormula (O/S-II), wherein R⁹ substitutes a hydrogen atom bound to a ringcarbon atom of ring A, each such R⁹ may be independently selected fromthe group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰, and/or any two R⁹ which are bound tothe same carbon atom of ring A may join together to form ═X. In any ofthe above embodiments of the spiroquinoxaline derivative of formula(O/S-II), wherein R⁹ substitutes a hydrogen atom bound to a ring carbonatom of ring A, each such R⁹ may be independently selected from thegroup consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,3-, 5-, 6- or 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)SR¹¹,—C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹, —OC(═O)R¹¹, —OC(═S)R¹¹,—N(R¹⁴)C(═O)N(R¹⁴)(R¹¹), and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein eachof the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-,6- or 7-membered heterocyclyl groups is optionally substituted with 1,2, or 3 independently selected R³⁰, and/or any two R⁹ which are bound tothe same carbon atom of ring A may join together to form ═O or ═S. Inone embodiment, each R⁹ when substituting a hydrogen atom bound to aring carbon atom of ring A is independently selected from the groupconsisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituentselected from the group consisting of —OH, —O(C₁₋₃ alkyl),—NH_(2-z)(CH₃)_(z), morpholinyl (e.g., 4-morpholinyl), piperazinyl(e.g., 1-piperazinyl), and N-methylpiperazinyl (e.g.,4-methylpiperazin-1-yl); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; cyclopropyl; 4-morpholinyl;homomorpholinyl; 4-piperidinyl; homopiperidinyl; 4-piperazinyl;homopiperazinyl; 4-methyl-piperazin-1-yl; N-methyl-homopiperazinyl;halogen; —CN; —OH; ═O; —O(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃alkyl); —S(O)₂(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl. In one embodiment, each R⁹ when substituting ahydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;tert-butyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—O(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —CH₂CF₃;—CH₂CHF₂; —CH₂CH₂F; —(CH₂)_(d)-(4-morpholinyl);—(CH₂)_(d)-(1-piperazinyl); —(CH₂)_(d)-(4-methylpiperazin-1-yl);4-morpholinyl; 4-piperazinyl; 4-methyl-piperazin-1-yl; halogen (inparticular, —F, —Cl, —Br); —NHC(═O)(C₁₋₃ alkyl optionally substitutedwith —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;halogen (in particular, —F, —Cl, —Br); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br);—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z);—S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃alkyl), wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl ismethyl, ethyl, propyl or isopropyl. In one embodiment, the ring carbonatoms of ring A are unsubstituted or each R⁹ substituting a hydrogenatom bound to a ring carbon atom is independently selected from thegroup consisting of C₁₋₄ alkyl (in particular methyl), —N(R¹²)(R¹³) (inparticular NH₂), and —N(R¹⁴)C(═O)R¹¹ (in particular NHC(O)CH₃). In oneembodiment, the ring carbon atoms of ring A are unsubstituted or onering carbon atom of ring A is substituted with one R⁹ being NH₂ or CH₃,or with two R⁹ being CH₃.

In any of the above embodiments of the spiroquinoxaline derivative offormula (O/S-II), wherein R⁹ is bound to a ring sulfur atom of ring A,each such R⁹ may be independently selected from the group consisting ofC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-memberedheterocyclyl, —OR¹¹, and ═O, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In any of the above embodiments of the spiroquinoxaline derivativeof formula (O/S-II), wherein R⁹ is bound to a ring sulfur atom of ringA, each such R⁹ may be independently selected from the group consistingof C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, 3-, 5-, 6-or 7-membered heterocyclyl, —OR¹¹, and ═O, wherein each of the C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or 6-memberedheteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-, 6- or7-membered heterocyclyl groups is optionally substituted with 1, 2, or 3independently selected R³⁰. In one embodiment, each R⁹ when bound to aring sulfur atom of ring A is independently selected from the groupconsisting of methyl, ethyl, C₃ alkyl, C₄ alkyl, —OR^(11′), and ═O,wherein R^(11′) is selected from the group consisting of —H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or6-membered aryl (e.g., phenyl), 5- or 6-membered heteroaryl, and 3- to7-membered heterocyclyl, wherein each of the methyl, ethyl, C₃ alkyl, C₄alkyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 7-membered heterocyclyl groups is optionally substituted with 1, 2,or 3 independently selected R^(30′) (R^(30′) is a 1^(st), 2^(nd), or3^(rd) level substituent as specified above (in particular one of thetypical 1^(st), 2^(nd), or 3^(rd) level substituents as specified above)and, in each case, may be selected from the group consisting of phenyl,furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, partially and completelyhydrogenated forms of the forgoing groups, morpholino, C₁₋₃ alkyl,halogen, —CF₃, —OH, —OCH₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH, and—C(═O)OCH₃, wherein z is 0, 1, or 2). In one embodiment, each R⁹ whenbound to a ring sulfur atom of ring A is independently selected from thegroup consisting of methyl; ethyl; isopropyl; benzyl; —OH; ═O; and—O(C₁₋₃ alkyl), wherein C₁₋₃ alkyl is methyl, ethyl, propyl orisopropyl. In one embodiment, the ring sulfur atom of ring A isunsubstituted or substituted with two ═O groups. In one embodiment, thering sulfur atom of ring A is unsubstituted or ring A contains onesulfur atom which is substituted with two ═O groups (i.e., ring Acontains the group —S(═O)₂—).

In one embodiment, the spiroquinoxaline derivative has the generalformula (O/S-III)

wherein R¹ to R⁵, ring A, E, and G are as defined above (in particularwith respect to formulas (O/S-I) and (O/S-II)) or below and L isselected from the group consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene,C₂₋₆ alkynylene, —(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—, wherein each of aand b is independently selected from an integer between 0 and 3, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2,o is 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, 1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment of the spiroquinoxaline derivative of formula(O/S-III), R¹ to R⁵, ring A, E, and G are as defined above (inparticular with respect to formulas (O/S-I) and (O/S-II)) or below and Lis selected from the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene,C₂₋₄ alkynylene, —(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b), wherein eachof a and b is independently selected from 0, 1, and 2, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2,o is 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₃ alkyl, 3-, 5-, 6- or 7-membered cycloalkyl,6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-memberedheterocyclyl, —O(C₁₋₃ alkyl), and —NHR²⁰, wherein each of the C₁₋₄alkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₃ alkyl, 3-, 5-, 6- or 7-memberedcycloalkyl, 6-membered aryl, 5- or 6-membered heteroaryl, and 3-, 5-, 6-or 7-membered heterocyclyl groups is optionally substituted with 1, 2,or 3 independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (O/S-III), R¹ to R⁵, ring A, E,and G are as defined above (in particular with respect to formulas(O/S-I) and (O/S-II)) or below and L is selected from the groupconsisting of C₁₋₃ alkylene, —(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b)—,wherein each of a and b is independently selected from 0 and 1, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1 or 2, n is 0, 1, or 2, ois 1 or 2, wherein if n is 0 then o is 1; Y is O, wherein each of theC₁₋₃ alkylene, 1,1-cyclopropylene, —(CH₂)_(m)—, and —(CH₂)_(n)— groupsis optionally substituted with 1, 2, or 3 independently selected R³⁰. Inone embodiment of the spiroquinoxaline derivative of formula (O/S-III),R¹ to R⁵, ring A, E, and G are as defined above (in particular withrespect to formulas (O/S-I) and (O/S-II)) or below and L is selectedfrom the group consisting of methylene; 1,1-ethylene; 1,2-ethylene(optionally substituted with one R³⁰ (such as phenyl) at position 2);trimethylene (—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 2,4-butandiyl;-1,1-cyclopropylene-; —(CH₂)-1,1-cyclopropylene;-1,1-cyclopropylene-(CH₂)—; —(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—;—(CH₂)₂O—; and —(CH₂)₃O— (such as methylene; 1,1-ethylene; 1,2-ethylene;trimethylene (—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene;and —(CH₂)₂O—, in particular, methylene). In one embodiment of thespiroquinoxaline derivative of formula (O/S-III), R¹ to R⁵, ring A, E,and G are as defined above (in particular with respect to formulas(O/S-I) and (O/S-II)) or below and L is selected from the groupconsisting of methylene; 1,1-ethylene; 1,2-ethylene; trimethylene(—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); -1,1-cyclopropylene-;—(CH₂)-1,1-cyclopropylene; -1,1-cyclopropylene-(CH₂)—;—(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—; —(CH₂)₂O—; and —(CH₂)₃O— (suchas methylene; 1,1-ethylene; 1,2-ethylene; trimethylene (—(CH₂)₃—);2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene; and —(CH₂)₂O—, inparticular, methylene). In one embodiment of the spiroquinoxalinederivative of formula (O/S-III), R¹ to R⁵, ring A, E, and G are asdefined above (in particular with respect to formulas (O/S-I) and(O/S-II)) or below and L is selected from the group consisting of C₁alkylene, C₂ alkylene (in particular 1,2-ethylene or 1,1-ethylene), C₃alkylene (in particular trimethylene), and C₄ alkylene (in particulartetramethylene or 2,4-butandiyl), each of which being optionallysubstituted with one R³⁰. In one embodiment of the spiroquinoxalinederivative of formula (O/S-III), R¹ to R⁵, ring A, E, and G are asdefined above (in particular with respect to formulas (O/S-I) and(O/S-II)) or below and L is selected from the group consisting ofmethylene, 1,1-ethylene, 1,2-ethylene, trimethylene, tetramethylene,2,4-butandiyl, and 2-phenyl-1,2-ethylene (—CH₂—CH(C₆H₅)—). In oneembodiment of the spiroquinoxaline derivative of formula (O/S-III), R¹to R⁵, ring A, E, and G are as defined above (in particular with respectto formulas (O/S-I) and (O/S-II)) or below and L is selected from thegroup consisting of methylene and 2-phenyl-1,2-ethylene(—CH₂—CH(C₆H₅)—).

In one embodiment, the spiroquinoxaline derivative has the generalformula (O/S-IV)

wherein R¹ to R⁵, ring A, E, and L are as defined above (in particularwith respect to formulas (O/S-I), (O/S-II) and (O/S-III)) or below and Gis phenyl which is either unsubstituted or substituted with 1, 2, 3, 4or 5 (such as between 1 to 4, or 1 to 3, or 1 or 2) independentlyselected R⁸. In any of the above embodiments (including those offormulas (O/S-I) to (O/S-III)), wherein G is substituted, R⁸ may be, ineach case, selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl,halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment of the spiroquinoxaline derivative of formula(O/S-IV), R¹ to R⁵, ring A, E, and L are as defined above (in particularwith respect to formulas (O/S-I), (O/S-II) and (O/S-III)) or below andR⁸ is, in each case, selected from the group consisting of C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or 6-memberedheteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, 3-, 5-, 6- or7-membered heterocyclyl, halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹,—N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹, —OC(═S)R¹¹, —N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and—N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹), wherein each of the C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3-,5-, 6- or 7-membered cycloalkyl, and 3-, 5-, 6- or 7-memberedheterocyclyl groups is optionally substituted with 1, 2, or 3independently selected R³⁰. In one embodiment of the spiroquinoxalinederivative of formula (O/S-IV), R¹ to R⁵, ring A, E, and L are asdefined above (in particular with respect to formulas (O/S-I), (O/S-II)and (O/S-III)) or below and R⁸ is, in each case, selected from the groupconsisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituentselected from the group consisting of —OH, —O(C₁₋₃ alkyl), and—NH_(2-z)(CH₃)_(z); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl;cyclopropyl; 5-membered heterocyclyl (such as pyrrolidinyl);4-morpholinyl; homomorpholinyl; 4-piperidinyl; homopiperidinyl;4-piperazinyl; homopiperazinyl; N-methyl-piperazin-4-yl;N-methyl-homopiperazinyl; halogen; —CN; —OH; —O(C₁₋₃ alkyl); —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; —O-phenyl; —NH₂; —NH(C₁₋₃alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl); —S(O)₂(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z);—NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and—N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2and C₁₋₃ alkyl is methyl, ethyl, propyl or isopropyl and each of thephenyl, cyclopropyl, 5-membered heterocyclyl (such as pyrrolidinyl),4-morpholinyl, homomorpholinyl, 4-piperidinyl, homopiperidinyl,4-piperazinyl, homopiperazinyl, N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, and —O-phenyl groups is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃, —OH, —OCH₃, —SCH₃,—NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, wherein z is 0, 1, or 2.In one embodiment, each R⁸ is independently selected from the groupconsisting of methyl; ethyl; isopropyl; tert-butyl; phenyl; cyclopropyl;pyrrolidinyl (such as 4-pyrrolidinyl); —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F;halogen (in particular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl);—N(C₁₋₃ alkyl)₂; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH;—C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl);—S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃alkyl), wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl ismethyl, ethyl, propyl or isopropyl. In one embodiment, each R⁸ isindependently selected from the group consisting of methyl; ethyl;isopropyl; phenyl; cyclopropyl; pyrrolidinyl (such as 4-pyrrolidinyl);—(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br); —CN;—NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (O/S-IV), R¹ to R⁵, ring A, E, and L are asdefined above (in particular with respect to formulas (O/S-I), (O/S-II)and (O/S-III)) or below and G is either unsubstituted or substitutedwith 1, 2, or 3 R⁸, wherein R⁸ is, in each case, selected from the groupconsisting of C₁₋₄ alkyl (in particular methyl or tert-butyl); halogen(in particular F or Cl); —OR¹¹ (in particular —OCH₃); and C₁₋₄ alkylsubstituted with 1, 2, or 3 independently selected R³⁰ (in particular—CF₃). In one embodiment of the spiroquinoxaline derivative of formula(O/S-IV), R¹ to R⁵, ring A, E, and L are as defined above (in particularwith respect to formulas (O/S-I), (O/S-II) and (O/S-III)) or below and Gis either unsubstituted or substituted with 1 or 2 R⁸ each independentlyselected from the group consisting of methyl, F, Cl, —OCH₃, and —CF₃. Inone embodiment of the spiroquinoxaline derivative of formula (O/S-IV),R¹ to R⁵, ring A, E, and L are as defined above (in particular withrespect to formulas (O/S-I), (O/S-II) and (O/S-III)) or below and G isselected from the group consisting of unsubstituted phenyl, fluorophenyl(in particular 3-fluorophenyl), chlorophenyl (in particular 2-, 3- or4-chlorophenyl), methylphenyl (in particular 2- or 3-methylphenyl),tert-butylphenyl (in particular 4-tert-butylphenyl), methoxyphenyl (inparticular 3-methoxyphenyl), (trifluoromethyl)phenyl (in particular 3-or 4-(trifluoromethyl)phenyl), difluorophenyl (in particular 2,4- or2,6-difluorophenyl), dichlorophenyl (in particular 2,4- or3,4-dichlorophenyl), chlorofluorophenyl (in particular4-chloro-2-fluorophenyl), and dimethylphenyl (in particular3,5-dimetylphenyl). In one embodiment of the spiroquinoxaline derivativeof formula (O/S-IV), R¹ to R⁵, ring A, E, and L are as defined above (inparticular with respect to formulas (O/S-I), (O/S-II) and (O/S-III)) orbelow and G is selected from the group consisting of unsubstitutedphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl,3-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 3,4-dichlorophenyl,4-chloro-2-fluorophenyl, and 3,5-dimetylphenyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (O/S-V)

wherein R¹, ring A, E, L and G are as defined above (in particular withrespect to formulas (O/S-I), (O/S-II), (O/S-III) and (O/S-IV)) or belowand each of R², R³, R⁴, and R⁵ is H. In one embodiment of thespiroquinoxaline derivative of formula (O/S-V), R¹, ring A, E, L and Gare as defined above (in particular with respect to formulas (O/S-I),(O/S-II), (O/S-III) and (O/S-IV)) or below and at least one of R², R³,R⁴, and R⁵ is different from H. For example, in one embodiment R² isdifferent from H and each of R³, R⁴, and R⁵ is H; or R³ is differentfrom H and each of R², R⁴, and R⁵ is H; or R⁴ is different from H andeach of R², R³, and R⁵ is H; or R⁵ is different from H and each of R²,R³, and R⁴ is H; or both of R² and R³ are different from H and both ofR⁴ and R⁵ are H; or both of R² and R⁴ are different from H and both ofR³ and R⁵ are H; or both of R² and R⁵ are different from H (preferablyin this embodiment R² and R⁵ are the same) and both of R³ and R⁴ are H;or both of R³ and R⁴ are different from H (preferably in this embodimentR³ and R⁴ are the same) and both of R² and R⁵ are H; or each of R², R³,and R⁴ is different from H and R⁵ is H; or each of R², R³, and R⁵ isdifferent from H and R⁴ is H; or each of R², R⁴, and R⁵ is differentfrom H and R³ is H; or each of R³, R⁴, and R⁵ is different from H and R²is H; or each of R², R³, R⁴, and R⁵ is different from H. In any of theabove embodiments, it is preferred that R² and R⁵ are the same and/or R³and R⁴ are the same.

In any of the above embodiments (in particular with respect to formulas(O/S-I), (O/S-II), (O/S-III), (O/S-IV), and (O/S-V)), each of R² to R⁵,if it does not join together with another of R² to R⁵ to form a ring, isindependently selected from the group consisting of —H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl,halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment, each of R², R³, R⁴, and R⁵, if it does not jointogether with another of R² to R⁵ to form a ring, may be independentlyselected from the group consisting of —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or7-membered cycloalkyl, 3-, 5-, 6- or 7-membered heterocyclyl, halogen,—CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹,—OC(═S)R¹¹, —N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹),wherein each of the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,and 3-, 5-, 6- or 7-membered heterocyclyl groups is optionallysubstituted with 1, 2, or 3 independently selected R³⁰. In oneembodiment of the spiroquinoxaline derivative of formula (O/S-V), R¹,ring A, E, L and G are as defined above (in particular with respect toformulas (O/S-I), (O/S-II), (O/S-III), and (O/S-IV)) or below and eachof R², R³, R⁴, and R⁵, if it does not join together with another of R²to R⁵ to form a ring, is independently selected from the groupconsisting of H; C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituentselected from the group consisting of —OH, —O(C₁₋₃ alkyl), and—NH_(2-z)(CH₃)_(z); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl;cyclopropyl; 5-membered heterocyclyl; 4-morpholinyl; homomorpholinyl;4-piperidinyl; homopiperidinyl; 4-piperazinyl; homopiperazinyl;N-methyl-piperazin-4-yl; N-methyl-homopiperazinyl; halogen; —CN; —OH;—O(C₁₋₃ alkyl); —O(C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F)), such as —OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F;—O-phenyl; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl);—S(O)₂(C₁₋₃ alkyl optionally substituted with —NH_(2-z)(CH₃)_(z));—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl and each of the phenyl, cyclopropyl, 5-memberedheterocyclyl, 4-morpholinyl, homomorpholinyl, 4-piperidinyl,homopiperidinyl, 4-piperazinyl, homopiperazinyl,N-methyl-piperazin-4-yl, N-methyl-homopiperazinyl, and —O-phenyl groupsis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃,—OH, —OCH₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, whereinz is 0, 1, or 2. In one embodiment, each of R², R³, R⁴, and R⁵, if itdoes not join together with another of R² to R⁵ to form a ring, isindependently selected from the group consisting of H; methyl; ethyl;isopropyl; phenyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (inparticular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH, and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (O/S-V), R¹, ring A, E, L and G are as definedabove (in particular with respect to formulas (O/S-I), (O/S-II),(O/S-III), and (O/S-IV)) or below and R², R³, R⁴, and R⁵ areindependently selected from the group consisting of —H, C₁₋₄ alkyl, andhalogen, wherein the C₁₋₄ alkyl is optionally substituted with 1, 2, or3 independently selected R³⁰ (in particular wherein R² and R⁵ are each—H). In one embodiment of the spiroquinoxaline derivative of formula(O/S-V), R¹, ring A, E, L and G are as defined above (in particular withrespect to formulas (O/S-I), (O/S-II), (O/S-III), and (O/S-IV)) or belowand R², R³, R⁴, and R⁵ are independently selected from the groupconsisting of —H, methyl, F, Cl, and CF₃ (in particular wherein R² andR⁵ are each —H). In one embodiment of the spiroquinoxaline derivative offormula (O/S-V), R¹, ring A, E, L and G are as defined above (inparticular with respect to formulas (O/S-I), (O/S-II), (O/S-III), and(O/S-IV)) or below and R² and R⁵ are each —H; R³ is selected from thegroup consisting of —H, methyl, F, and Cl; and R⁴ is selected from thegroup consisting of —H, methyl, F, and Cl. In one embodiment of thespiroquinoxaline derivative of formula (O/S-V), R¹, ring A, E, L and Gare as defined above (in particular with respect to formulas (O/S-I),(O/S-II), (O/S-III), and (O/S-IV)) or below and (i) R² to R⁵ are each—H; or (ii) R² and R⁵ are each —H, and both of R³ and R⁴ are F, Cl, ormethyl.

In any of the above embodiments, wherein a ring is formed by (i) R² andR³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵, said ring preferably is a 3-to 7-membered ring (e.g., a ring having 5 or 6 members) which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰. The ring may be an aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N(R⁴⁰), wherein R⁴⁰ is selectedfrom the group consisting of R¹¹, —OR¹¹, —NH_(y)R²⁰ _(2-y), and—S(O)₁₋₂R¹¹, wherein R¹¹, R²⁰, and y are as defined above. In oneembodiment, the ring formed by (i) R² and R³, (ii) R³ and R⁴, and/or(iii) R⁴ and R⁵ is a 5- or 6-membered aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N, wherein at least oneheteroatom is N. In one embodiment, the ring formed by (i) R² and R³,(ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is selected from the groupconsisting of cyclopentadiene, furan, pyrrole, thiophene, imidazole,pyrazole, oxazole, isoxazole, thiazole, dioxole (e.g., 1,3-dioxole),benzene, pyridine, pyrazine, pyrimidine, pyridazine, dioxine (e.g.,1,4-dioxine), 1,2,3-triazine, 1,2,4-triazine, and di- or tetrahydroforms of each of the foregoing. In one embodiment, the ring formed (i)R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is cyclopentene (suchas 2,3-dihydrocyclopentadiene), dioxole (such as 1,3-dioxole, optionallysubstituted at position 2 with one or two halogen atoms (such as F)), ordioxine (such as 2,3-dihydro-[1,4]-dioxine). In one embodiment, thetotal number of rings formed by (i) R² and R³, (ii) R³ and R⁴, and/or(iii) R⁴ and R⁵ is 0 or 1. Thus, in the embodiment, wherein the totalnumber of rings formed by (i) R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴and R⁵ is 1, only two adjacent substituents (i.e., either (i) R² and R³,(ii) R³ and R⁴, or (iii) R⁴ and R⁵) join together with the atoms towhich they are attached to form a ring, wherein the ring is as definedin any of the above embodiments and the remaining of R² to R⁵ areselected from the particular groups of moieties specified above for thesituation that they do not join together to form a ring. For example,the remaining R² to R⁵ which do not join together to form a ring may beselected from —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰. In an alternative embodiment, R² to R⁵do not join together to form a ring.

In any of the above embodiments, R² and R⁵ may be the same and/or R³ andR⁴ may be the same.

In one embodiment of the spiroquinoxaline derivative of formula (O/S-V),R¹, ring A, E, L and G are as defined above (in particular with respectto formulas (O/S-I), (O/S-II), (O/S-III), and (O/S-IV)) or below and R²,R³, R⁴, and R⁵ are independently selected from the group consisting of—H, C₁₋₄ alkyl, and halogen, wherein the C₁₋₄ alkyl is optionallysubstituted with 1, 2, or 3 independently selected R³⁰ (in particularwherein R² and R⁵ are each —H), or R³ and R⁴ may join together with theatoms to which they are attached to form a 5- or 6-membered ring whichis optionally substituted with one or two independently selected R³⁰. Inone embodiment of the spiroquinoxaline derivative of formula (O/S-V),R¹, ring A, E, L and G are as defined above (in particular with respectto formulas (O/S-I), (O/S-II), (O/S-III), and (O/S-IV)) or below and R²,R³, R⁴, and R⁵ are independently selected from the group consisting of—H, methyl, F, Cl, and CF₃ (in particular wherein R² and R⁵ are each—H), or R³ and R⁴ may join together with the atoms to which they areattached to form a dioxole or dioxine ring which is optionallysubstituted with one or two independently selected halogens (inparticular F). In one embodiment of the spiroquinoxaline derivative offormula (O/S-V), R¹, ring A, E, L and G are as defined above (inparticular with respect to formulas (O/S-I), (O/S-II), (O/S-III), and(O/S-IV)) or below and R² and R⁵ are each —H; R³ is selected from thegroup consisting of —H, methyl, F, and Cl; and R⁴ is selected from thegroup consisting of —H, methyl, F, and Cl; or R³ and R⁴ may jointogether with the atoms to which they are attached to form a dioxole (inparticular 1,3-dioxole) or dioxine (in particular2,3-dihydro-[1,4]-dioxine) ring, wherein the dioxole ring is optionallysubstituted with two F. In one embodiment of the spiroquinoxalinederivative of formula (O/S-V), R¹, ring A, E, L and G are as definedabove (in particular with respect to formulas (O/S-I), (O/S-II),(O/S-III), and (O/S-IV)) or below and (i) R² to R⁵ are each —H; (ii) R²and R⁵ are each —H, and both of R³ and R⁴ are F, Cl, or methyl, or (iii)R² and R⁵ are each —H, and R³ and R⁴ join together with the atoms towhich they are attached to form a 2,2-difluoro-1,3-dioxole ring or a2,3-dihydro-[1,4]-dioxine ring.

In any of the above embodiments (in particular with respect to formulas(O/S-I), (O/S-II), (O/S-III), (O/S-IV), and (O/S-V)), R³⁰, in each case,may be a typical 1^(st), 2^(nd), or 3^(rd) level substituent asspecified above and may be independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5-, 6-,or 7-membered heterocyclyl, halogen, —CF₃, —CN, azido, —NO₂, —OH,—O(C₁₋₃ alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, such as 4-morpholinyl,homomorpholinyl, 4-piperidinyl, homopiperidinyl (i.e., azepanyl, inparticular 4-azepanyl), 4-piperazinyl, homopiperazinyl (i.e.,diazepanyl, in particular 2,4-diazepanyl), N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, —CH₂CH₂OCH₃, —OCH₂CH₂OCH₃,—CH₂CH₂NH_(2-z)(CH₃)_(z), —OCH₂CH₂NH_(2-z)(CH₃)_(z), —CF₃, —OCF₃.Alternatively, R³⁰ may be selected from the group consisting of phenyl,furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, partially and completelyhydrogenated forms of the forgoing groups, morpholino, C₁₋₃ alkyl,halogen, —CF₃, —OH, —OCH₃, —OCF₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH,and —C(═O)OCH₃, wherein z is 0, 1, or 2.

In one embodiment, the spiroquinoxaline derivative has the generalformula (C-I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof,whereinE is —N(R⁶)—;L is selected from the group consisting of C₁₋₁₀ alkylene, C₂₋₁₀alkenylene, C₂₋₁₀ alkynylene, 1,1-(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—,wherein each of a and b is independently selected from an integerbetween 0 and 3, and —(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is aninteger between 1 and 6, n is an integer between 0 and 3, o is aninteger between 1 and 3, wherein if n is 0 then o is 1; Y isindependently selected from O, S, and —N(R⁷)—; and each of the C₁₋₁₀alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, and —(CH₂)_(n)— groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, or —(CH₂)_(n)— group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;G is phenyl, optionally substituted with 1, 2, 3, 4 or 5 independentlyselected R⁸;ring A is a monocyclic 3- to 10-membered cycloalkylene, optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹;R¹ is H;R², R³, R⁴, and R⁵ are independently selected from the group consistingof —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³),—N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or2) independently selected R³⁰;or R² and R³ may join together with the atoms to which they are attachedto form a ring which is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the ring, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1to 3, or 1 or 2) independently selected R³⁰; R³ and R⁴ may join togetherwith the atoms to which they are attached to form a ring which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰; and/or R⁴ and R⁵ may join together with theatoms to which they are attached to form a ring which is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁶ is H;R⁷ is selected from the group consisting of —H, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R⁸ is, in each case, selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen,—CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹,—S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰;R⁹ is independently selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen,—CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹,—OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹) S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³),—C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of thealkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclylgroups is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R³⁰, and/or any two R⁹ which are boundto the same carbon atom of ring A may join together to form ═X;X is independently selected from O, S, and N(R¹⁴);R¹¹ is, in each case, selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹² and R¹³ are, in each case, independently selected from the groupconsisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl, or R¹² and R¹³ may join together with the nitrogenatom to which they are attached to form the group —N═CR¹⁵R¹⁶, whereineach of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or1 to 3, or 1 or 2) independently selected R³⁰;R¹⁴ is independently selected from the group consisting of —H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR¹¹,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;R¹⁵ and R¹⁶ are independently selected from the group consisting of —H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and—NH_(y)R²⁰ _(2-y), or R¹⁵ and R¹⁶ may join together with the atom towhich they are attached to form a ring which is optionally substitutedwith one or more (such as 1 to the maximum number of hydrogen atomsbound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more (such as 1 to the maximum number of hydrogen atoms bound to thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclylgroup, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R³⁰;y is an integer from 0 to 2;R²⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclylgroups is optionally substituted with one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3,or 1 or 2) independently selected R³⁰; and R³⁰ is a 1^(st) levelsubstituent and is, in each case, independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR⁷¹, —N(R⁷²)(R⁷³),—S(O)₀₋₂R⁷¹, —S(O)₁₋₂OR⁷¹, —OS(O)₁₋₂R⁷¹, —OS(O)₁₋₂OR⁷¹,—S(O)₁₋₂N(R⁷²)(R⁷³), —OS(O)₁₋₂N(R⁷²)(R⁷³), —N(R⁷¹)S(O)₁₋₂R⁷¹,—NR⁷¹S(O)₁₋₂OR⁷¹, —NR⁷¹S(O)₁₋₂N(R⁷²)(R⁷³), —C(═X¹)R⁷¹, —C(═X¹)X¹R⁷¹,—X¹C(═X¹)R⁷¹, and —X¹C(═X¹)X¹R⁷¹, and/or any two R³⁰ which are bound tothe same carbon atom of a cycloalkyl or heterocyclyl group may jointogether to form ═X¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups being a 1^(st) levelsubstituent is optionally substituted by one or more (such as 1 to themaximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, or heterocyclyl group being a 1^(st) levelsubstituent, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such asbetween 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) 2^(nd) level substituents,wherein said 2^(nd) level substituent is, in each case, independentlyselected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF₃,—CN, azido, —NO₂, —OR⁸¹, —N(R⁸²)(R⁸³), —S(O)₀₋₂R⁸¹, —S(O)₁₋₂OR⁸¹,—OS(O)₁₋₂R⁸¹, —OS(O)₁₋₂OR⁸¹, —S(O)₁₋₂N(R⁸²)(R⁸³), —OS(O)₁₋₂N(R⁸²)(R⁸³),—N(R⁸¹)S(O)₁₋₂R⁸¹, —NR⁸¹S(O)₁₋₂OR⁸¹, —NR⁸¹S(O)₁₋₂N(R⁸²)(R⁸³),—C(═X²)R⁸¹, —C(═X²)X²R⁸¹, —X²C(═X²)R⁸¹, and —X²C(═X²)X²R⁸¹, and/or anytwo 2^(nd) level substituents which are bound to the same carbon atom ofa cycloalkyl or heterocyclyl group being a 1^(st) level substituent mayjoin together to form ═X², wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3-to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl groupsbeing a 2^(nd) level substituent is optionally substituted with one ormore (such as 1 to the maximum number of hydrogen atoms bound to theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to14-membered heteroaryl, 3- to 14-membered cycloalkyl, or 3- to14-membered heterocyclyl group being a 2^(nd) level substituent, e.g.,1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4,or 1 to 3, or 1 or 2) 3^(rd) level substituents, wherein said 3^(rd)level substituent is, in each case, independently selected from thegroup consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH,—O(C₁₋₃ alkyl), —OCF₃, —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3^(rd) levelsubstituents which are bound to the same carbon atom of a 3- to14-membered cycloalkyl or heterocyclyl group being a 2^(nd) levelsubstituent may join together to form ═O, ═S, ═NH, or ═N(C₁₋₃ alkyl);whereinR⁷¹, R⁷², and R⁷³ are independently selected from the group consistingof —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 7-membered heterocyclyl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl;R⁸¹, R⁸², and R⁸³ are independently selected from the group consistingof —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3- to 6-memberedcycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-to 6-membered heterocyclyl, wherein each of the C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclylgroups is optionally substituted with one, two or three substituentsselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN,azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂,—NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)(C₁₋₃ alkyl), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl; andX¹ and X² are independently selected from O, S, and N(R⁸⁴), whereinR^(s4) is —H or C₁₋₃ alkyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (C-II)

wherein R¹ to R⁵, E, L and G are as defined above or below and theoptionally substituted monocyclic ring A is 3- to 8-membered, preferably4-, 5-, 6- or 7-membered, more preferably 6- or 7-membered. In oneembodiment of the spiroquinoxaline derivative of formula (C-II), ring Aas such is unsaturated (i.e., the 3 to 10 members of ring A constitute1, 2, or 3 (preferably 1 or 2, most preferably 1) double bonds withinthe ring) but is not aromatic. In an alternative embodiment of thespiroquinoxaline derivative of formula (C-II), ring A is saturated(i.e., ring A as such is free of unsaturation within the ring); however,if ring A is substituted by one or more (such as 1 to the maximum numberof hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) R⁹, R⁹may be unsaturated (i.e., may contain double and/or triple bonds and/orone or more (e.g., 1, 2. or 3) aromatic ring(s)). In any of the aboveembodiments of the spiroquinoxaline derivative of formula (C-II), ring Amay be selected from the group consisting of cyclohexylene,cycloheptylene, cyclopropylene, cyclobutylene, cyclopentylene,cyclooctylene, cyclohexenylene, cycloheptenylene, cyclopentenylene,cyclooctenylene and their regioisomers, each of which is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or upto 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹. In one embodiment of the spiroquinoxalinederivative of formula (C-II), ring A is selected from the groupconsisting of cyclohexylene, cycloheptylene, cyclopropylene,cyclobutylene, cyclopentylene, and cyclooctylene, each of which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to ring A, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R⁹. In one embodiment of the spiroquinoxalinederivative of formula (C-II), ring A is selected from the groupconsisting of cyclohexylene, cycloheptylene, cyclopentylene, andcyclooctylene, each of which is optionally substituted with one or more(such as 1 to the maximum number of hydrogen atoms bound to ring A,e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1to 4, or 1 to 3, or 1 or 2) independently selected R⁹.

In any of the above embodiments of the spiroquinoxaline derivative offormula (C-II), ring A may be unsubstituted.

In any of the above embodiments of the spiroquinoxaline derivative offormula (C-II), wherein ring A is substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to ring A, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1to 3, or 1 or 2) independently selected R⁹, each such R⁹ may beindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl,halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰, and/or any two R⁹ which are bound to the same carbon atom of ring Amay join together to form ═X. In any of the above embodiments of thespiroquinoxaline derivative of formula (C-II), each R⁹ may beindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3-,5-, 6- or 7-membered cycloalkyl, 3-, 5-, 6- or 7-membered heterocyclyl,halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹) S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹,—OC(═S)R¹¹, —N(R¹⁴)C(═O)N(R¹⁴)(R¹¹), and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹),wherein each of the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,and 3-, 5-, 6- or 7-membered heterocyclyl groups is optionallysubstituted with 1, 2, or 3 independently selected R³⁰, and/or any twoR⁹ which are bound to the same carbon atom of ring A may join togetherto form ═O or ═S. In one embodiment, each R⁹ is independently selectedfrom the group consisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1substituent selected from the group consisting of —OH, —O(C₁₋₃ alkyl),—NH_(2-z)(CH₃)_(z), morpholinyl (e.g., 4-morpholinyl), piperazinyl(e.g., 1-piperazinyl), and N-methylpiperazinyl (e.g.,4-methylpiperazin-1-yl); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; cyclopropyl; 4-morpholinyl;homomorpholinyl; 4-piperidinyl; homopiperidinyl; 4-piperazinyl;homopiperazinyl; 4-methyl-piperazin-1-yl; N-methyl-homopiperazinyl;halogen; —CN; —OH; ═O; —O(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃alkyl); —S(O)₂(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl. In one embodiment, each R⁹ is independentlyselected from the group consisting of methyl; ethyl; isopropyl;tert-butyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—O(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —CH₂CF₃;—CH₂CHF₂; —CH₂CH₂F; —(CH₂)_(d)-(4-morpholinyl);—(CH₂)_(d)-(1-piperazinyl); —(CH₂)_(d)-(4-methylpiperazin-1-yl);4-morpholinyl; 4-piperazinyl; 4-methyl-piperazin-1-yl; halogen (inparticular, —F, —Cl, —Br); —NHC(═O)(C₁₋₃ alkyl optionally substitutedwith —NH_(2-z)(CH₃)_(z)); —NHC(═O)NH_(2-z)(CH₃)_(z); —NHS(O)₂(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;halogen (in particular, —F, —Cl, —Br); —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment, each R⁹ when substitutinga hydrogen atom bound to a ring carbon atom of ring A is independentlyselected from the group consisting of methyl; ethyl; isopropyl;cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br);—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z);—S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃alkyl), wherein z is 0, 1, or 2; d is 1, 2, or 3; and C₁₋₃ alkyl ismethyl, ethyl, propyl or isopropyl. In one embodiment, the ring carbonatoms of ring A are unsubstituted or each R⁹ substituting a hydrogenatom bound to a ring carbon atom is independently selected from thegroup consisting of C₁₋₄ alkyl (in particular methyl), —N(R¹²)(R¹³) (inparticular NH₂), and —N(R¹⁴)C(═O)R¹¹ (in particular NHC(O)CH₃). In oneembodiment, the ring carbon atoms of ring A are unsubstituted or onering carbon atom of ring A is substituted with one R⁹ being NH₂ or CH₃,or with two R⁹ being CH₃.

In any of the above embodiments of the spiroquinoxaline derivative offormula (C-II), wherein ring A is substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to ring A, e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1to 3, or 1 or 2) independently selected R⁹, preferably R⁹ is bound toring A at position 3 if ring A is 4-membered; at position 3 or 4 if ringA is 5-membered; at position 3, 4, or 5 if ring A is 6-membered; atposition 3, 4, 5, or 6 if ring A is 7-membered; or at position 3, 4, 5,6, or 7 if ring A is 8-membered. In one embodiment, in particular ifring A is substituted with 1 or 2 independently selected R⁹, R⁹ is boundto ring A at position 3 if ring A is 4- or 5-membered; at position 3 or4 (preferably 4) if ring A is 6- or 7-membered; or at position 3, 4, or5 if ring A is 8-membered.

In one embodiment, the spiroquinoxaline derivative has the generalformula (C-III)

wherein R¹ to R⁵, ring A, E, and G are as defined above (in particularwith respect to formulas (C-I) and (C-II)) or below and L is selectedfrom the group consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, —(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—, wherein each of a andb is independently selected from an integer between 0 and 3, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2,o is 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered heterocyclyl, —OR¹¹, and —NHR²⁰, whereineach of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, 1,1-cyclopropylene, —(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment of the spiroquinoxaline derivative of formula(C-III), R¹ to R⁵, ring A, E, and G are as defined above (in particularwith respect to formulas (C-I) and (C-II)) or below and L is selectedfrom the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene, C₂₋₄alkynylene, —(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b), wherein each of aand b is independently selected from 0, 1, and 2, and—(CH₂)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1, 2, or 3, n is 0, 1, or 2, ois 1, 2, or 3, wherein if n is 0 then o is 1; Y is independentlyselected from O, S, and —N(R^(7′))—, wherein R^(7′) is selected from thegroup consisting of —H, C₁₋₃ alkyl, 3-, 5-, 6- or 7-membered cycloalkyl,6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-memberedheterocyclyl, —O(C₁₋₃ alkyl), and —NHR²⁰, wherein each of the C₁₋₄alkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene, 1,1-cyclopropylene,—(CH₂)_(m)—, —(CH₂)_(n)—, C₁₋₃ alkyl, 3-, 5-, 6- or 7-memberedcycloalkyl, 6-membered aryl, 5- or 6-membered heteroaryl, and 3-, 5-, 6-or 7-membered heterocyclyl groups is optionally substituted with 1, 2,or 3 independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (C-III), R¹ to R⁵, ring A, E, andG are as defined above (in particular with respect to formulas (C-I) and(C-II)) or below and L is selected from the group consisting of C₁₋₃alkylene, —(CH₂)_(a)-1,1-cyclopropylene-(CH₂)_(b)—, wherein each of aand b is independently selected from 0 and 1, and—(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is 1 or 2, n is 0, 1, or 2, ois 1 or 2, wherein if n is 0 then o is 1; Y is 0, wherein each of theC₁₋₃ alkylene, 1,1-cyclopropylene, —(CH₂)_(m)—, and —(CH₂)_(n)— groupsis optionally substituted with 1, 2, or 3 independently selected R³⁰. Inone embodiment of the spiroquinoxaline derivative of formula (C-III), R¹to R⁵, ring A, E, and G are as defined above (in particular with respectto formulas (C-I) and (CII)) or below and L is selected from the groupconsisting of methylene; 1,1-ethylene; 1,2-ethylene (optionallysubstituted with one R³⁰ (such as phenyl) at position 2); trimethylene(—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 2,4-butandiyl;-1,1-cyclopropylene-; —(CH₂)-1,1-cyclopropylene;-1,1-cyclopropylene-(CH₂)—; —(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—;—(CH₂)₂O—; and —(CH₂)₃O— (such as methylene; 1,1-ethylene; 1,2-ethylene;trimethylene (—(CH₂)₃—); 2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene;and —(CH₂)₂O—, in particular, methylene). In one embodiment of thespiroquinoxaline derivative of formula (C-III), R¹ to R⁵, ring A, E, andG are as defined above (in particular with respect to formulas (C-I) and(C-II)) or below and L is selected from the group consisting ofmethylene; 1,1-ethylene; 1,2-ethylene; trimethylene (—(CH₂)₃—);2,2-propylene (—C(CH₃)₂—); -1,1-cyclopropylene-;—(CH₂)-1,1-cyclopropylene; -1,1-cyclopropylene-(CH₂)—;—(CH₂)-1,1-cyclopropylene-(CH₂)—; —CH₂O—; —(CH₂)₂O—; and —(CH₂)₃O— (suchas methylene; 1,1-ethylene; 1,2-ethylene; trimethylene (—(CH₂)₃—);2,2-propylene (—C(CH₃)₂—); 1,1-cyclopropylene; and —(CH₂)₂O—, inparticular, methylene). In one embodiment of the spiroquinoxalinederivative of formula (C-III), R¹ to R⁵, ring A, E, and G are as definedabove (in particular with respect to formulas (C-I) and (C-II)) or belowand L is selected from the group consisting of C₁ alkylene, C₂ alkylene(in particular 1,2-ethylene or 1,1-ethylene), C₃ alkylene (in particulartrimethylene), and C₄ alkylene (in particular tetramethylene or2,4-butandiyl), each of which being optionally substituted with one R³⁰.In one embodiment of the spiroquinoxaline derivative of formula (C-III),R¹ to R⁵, ring A, E, and G are as defined above (in particular withrespect to formulas (C-I) and (C-II)) or below and L is selected fromthe group consisting of methylene, 1,1-ethylene, 1,2-ethylene,trimethylene, tetramethylene, 2,4-butandiyl, and 2-phenyl-1,2-ethylene(—CH₂—CH(C₆H₅)—). In one embodiment of the spiroquinoxaline derivativeof formula (C-III), R¹ to R⁵, ring A, E, and G are as defined above (inparticular with respect to formulas (C-I) and (C-II)) or below and L isselected from the group consisting of methylene and2-phenyl-1,2-ethylene (—CH₂—CH(C₆H₅)—).

In one embodiment, the spiroquinoxaline derivative has the generalformula (C-IV)

wherein R¹ to R⁵, ring A, E, and L are as defined above (in particularwith respect to formulas (C-I), (C-II) and (C-III)) or below and G isphenyl which is either unsubstituted or substituted with 1, 2, 3, 4 or 5(such as between 1 to 4, or 1 to 3, or 1 or 2) independently selected R.In any of the above embodiments (including those of formulas (C-I) to(C-III)), wherein G is substituted, R⁸ may be, in each case, selectedfrom the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (C-IV), R¹ to R⁵, ring A, E, andL are as defined above (in particular with respect to formulas (C-I),(C-II) and (C-III)) or below and R⁸ is, in each case, selected from thegroup consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,3-, 5-, 6- or 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R, —C(═O)OR¹¹, —C(═O)SR¹¹,—C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹, —OC(═S)R¹¹,—N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹), wherein each ofthe C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-membered aryl, 5- or6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl, and 3-, 5-,6- or 7-membered heterocyclyl groups is optionally substituted with 1,2, or 3 independently selected R³⁰. In one embodiment of thespiroquinoxaline derivative of formula (C-IV), R¹ to R⁵, ring A, E, andL are as defined above (in particular with respect to formulas (C-I),(C-II) and (C-III)) or below and R⁸ is, in each case, selected from thegroup consisting of C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1substituent selected from the group consisting of —OH, —O(C₁₋₃ alkyl),and —NH_(2-z)(CH₃)_(z); C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F), such as —CF₃, —CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl;cyclopropyl; 5-membered heterocyclyl (such as pyrrolidinyl);4-morpholinyl; homomorpholinyl; 4-piperidinyl; homopiperidinyl;4-piperazinyl; homopiperazinyl; N-methyl-piperazin-4-yl;N-methyl-homopiperazinyl; halogen; —CN; —OH; —O(C₁₋₃ alkyl); —O(C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F)), such as—OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F; —O-phenyl; —NH₂; —NH(C₁₋₃alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl); —S(O)₂(C₁₋₃ alkyl optionallysubstituted with —NH_(2-z)(CH₃)_(z)); —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z);—NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyl optionally substituted with—NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and—N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2and C₁₋₃ alkyl is methyl, ethyl, propyl or isopropyl and each of thephenyl, cyclopropyl, 5-membered heterocyclyl (such as pyrrolidinyl),4-morpholinyl, homomorpholinyl, 4-piperidinyl, homopiperidinyl,4-piperazinyl, homopiperazinyl, N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, and —O-phenyl groups is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃, —OH, —OCH₃, —SCH₃,—NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, wherein z is 0, 1, or 2.In one embodiment, each R⁸ is independently selected from the groupconsisting of methyl; ethyl; isopropyl; tert-butyl; phenyl; cyclopropyl;pyrrolidinyl (such as 4-pyrrolidinyl); —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F;halogen (in particular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl);—N(C₁₋₃ alkyl)₂; —C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH;—C(═O)O(C₁₋₃ alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃alkyl); —S(O)₂(C₁₋₃ alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and—O(C₁₋₃ alkyl), wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkylis methyl, ethyl, propyl or isopropyl. In one embodiment, each R⁸ isindependently selected from the group consisting of methyl; ethyl;isopropyl; phenyl; cyclopropyl; pyrrolidinyl (such as 4-pyrrolidinyl);—(CH₂)_(d)—NH_(2-z)(CH₃)_(z); —(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —O-phenyl;—CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (in particular, —F, —Cl, —Br); —CN;—NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —C(═O)CH₃;—C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)OH; —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH; and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (C-IV), R¹ to R⁵, ring A, E, and L are as definedabove (in particular with respect to formulas (C-I), (C-II) and (C-III))or below and G is either unsubstituted or substituted with 1, 2, or 3R⁸, wherein R⁸ is, in each case, selected from the group consisting ofC₁₋₄ alkyl (in particular methyl or tert-butyl); halogen (in particularF or Cl); —OR¹¹ (in particular —OCH₃); and C₁₋₄ alkyl substituted with1, 2, or 3 independently selected R³⁰ (in particular —CF₃). In oneembodiment of the spiroquinoxaline derivative of formula (C-IV), R¹ toR⁵, ring A, E, and L are as defined above (in particular with respect toformulas (C-I), (C-II) and (C-III)) or below and G is eitherunsubstituted or substituted with 1 or 2 R⁸ each independently selectedfrom the group consisting of methyl, F, Cl, —OCH₃, and —CF₃. In oneembodiment of the spiroquinoxaline derivative of formula (C-IV), R¹ toR⁵, ring A, E, and L are as defined above (in particular with respect toformulas (C-I), (C-II) and (C-III)) or below and G is selected from thegroup consisting of unsubstituted phenyl, fluorophenyl (in particular3-fluorophenyl), chlorophenyl (in particular 2-, 3- or 4-chlorophenyl),methylphenyl (in particular 2- or 3-methylphenyl), tert-butylphenyl (inparticular 4-tert-butylphenyl), methoxyphenyl (in particular3-methoxyphenyl), (trifluoromethyl)phenyl (in particular 3- or4-(trifluoromethyl)phenyl), difluorophenyl (in particular 2,4- or2,6-difluorophenyl), dichlorophenyl (in particular 2,4- or3,4-dichlorophenyl), chlorofluorophenyl (in particular4-chloro-2-fluorophenyl), and dimethylphenyl (in particular3,5-dimetylphenyl). In one embodiment of the spiroquinoxaline derivativeof formula (C-IV), R¹ to R⁵, ring A, E, and L are as defined above (inparticular with respect to formulas (C-I), (C-II) and (C-III)) or belowand G is selected from the group consisting of unsubstituted phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl,3-(trifluoromethyl)phenyl, 2,6-difluorophenyl, 3,4-dichlorophenyl,4-chloro-2-fluorophenyl, and 3,5-dimetylphenyl.

In one embodiment, the spiroquinoxaline derivative has the generalformula (C-V)

wherein R¹, ring A, E, L and G are as defined above (in particular withrespect to formulas (C-I), (C-II), (C-III) and (C-IV)) or below and eachof R², R³, R⁴, and R⁵ is H. In one embodiment of the spiroquinoxalinederivative of formula (C-V), R¹, ring A, E, L and G are as defined above(in particular with respect to formulas (C-I), (C-II), (C-III) and(C-IV)) or below and at least one of R², R³, R⁴, and R⁵ is differentfrom H. For example, in one embodiment R² is different from H and eachof R³, R⁴, and R⁵ is H; or R³ is different from H and each of R², R⁴,and R⁵ is H; or R⁴ is different from H and each of R², R³, and R⁵ is H;or R⁵ is different from H and each of R², R³, and R⁴ is H; or both of R²and R³ are different from H and both of R⁴ and R⁵ are H; or both of R²and R⁴ are different from H and both of R³ and R⁵ are H; or both of R²and R⁵ are different from H (preferably in this embodiment R² and R⁵ arethe same) and both of R³ and R⁴ are H; or both of R³ and R⁴ aredifferent from H (preferably in this embodiment R³ and R⁴ are the same)and both of R² and R⁵ are H; or each of R², R³, and R⁴ is different fromH and R⁵ is H; or each of R², R³, and R⁵ is different from H and R⁴ isH; or each of R², R⁴, and R⁵ is different from H and R³ is H; or each ofR³, R⁴, and R⁵ is different from H and R² is H; or each of R², R³, R⁴,and R⁵ is different from H. In any of the above embodiments, it ispreferred that R² and R⁵ are the same and/or R³ and R⁴ are the same.

In any of the above embodiments (in particular with respect to formulas(C-I), (C-II), (C-III), (C-IV), and (C-V)), each of R² to R⁵, if it doesnot join together with another of R² to R⁵ to form a ring, isindependently selected from the group consisting of —H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl,halogen, —CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-memberedheterocyclyl groups is optionally substituted with one or more (such as1 to the maximum number of hydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, 3- to 7-membered cycloalkyl, or 3- to 7-memberedheterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, suchas between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selectedR³⁰. In one embodiment, each of R², R³, R⁴, and R⁵, if it does not jointogether with another of R² to R⁵ to form a ring, may be independentlyselected from the group consisting of —H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or7-membered cycloalkyl, 3-, 5-, 6- or 7-membered heterocyclyl, halogen,—CN, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)SR¹¹, —C(═O)N(R¹⁴)(R¹¹), —C(═S)OR¹¹, —N(R¹⁴)C(═O)R¹¹, —OC(═O)R¹¹,—OC(═S)R¹¹, —N(R¹⁴)C(═O)N(R¹⁴)(R¹¹) and —N(R¹⁴)C(═N(R¹⁴))N(R¹⁴)(R¹¹),wherein each of the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 6-memberedaryl, 5- or 6-membered heteroaryl, 3-, 5-, 6- or 7-membered cycloalkyl,and 3-, 5-, 6- or 7-membered heterocyclyl groups is optionallysubstituted with 1, 2, or 3 independently selected R³⁰. In oneembodiment of the spiroquinoxaline derivative of formula (C-V), R¹, ringA, E, L and G are as defined above (in particular with respect toformulas (C-I), (C-II), (C-III), and (C-IV)) or below and each of R²,R³, R⁴, and R⁵, if it does not join together with another of R² to R⁵ toform a ring, is independently selected from the group consisting of H;C₁₋₄ alkyl; C₁₋₄ alkyl substituted with 1 substituent selected from thegroup consisting of —OH, —O(C₁₋₃ alkyl), and —NH_(2-z)(CH₃)_(z); C₁₋₄alkyl substituted with 1, 2, or 3 halogen (preferably F), such as —CF₃,—CH₂CF₃, —CH₂CHF₂, or —CH₂CH₂F; phenyl; cyclopropyl; 5-memberedheterocyclyl; 4-morpholinyl; homomorpholinyl; 4-piperidinyl;homopiperidinyl; 4-piperazinyl; homopiperazinyl;N-methyl-piperazin-4-yl; N-methyl-homopiperazinyl; halogen; —CN; —OH;—O(C₁₋₃ alkyl); —O(C₁₋₄ alkyl substituted with 1, 2, or 3 halogen(preferably F)), such as —OCF₃, —OCH₂CF₃, —OCH₂CHF₂, or —OCH₂CH₂F;—O-phenyl; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂; —S(C₁₋₃ alkyl);—S(O)₂(C₁₋₃ alkyl optionally substituted with —NH_(2-z)(CH₃)_(z));—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z); —NHS(O)₂(C₁₋₃ alkyl); —C(═O)(C₁₋₃ alkyloptionally substituted with —NH_(2-z)(CH₃)_(z)); —C(═O)OH; —C(═O)O(C₁₋₃alkyl); —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl);—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z); and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl and each of the phenyl, cyclopropyl, 5-memberedheterocyclyl, 4-morpholinyl, homomorpholinyl, 4-piperidinyl,homopiperidinyl, 4-piperazinyl, homopiperazinyl,N-methyl-piperazin-4-yl, N-methyl-homopiperazinyl, and —O-phenyl groupsis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of C₁₋₃ alkyl, halogen, —CF₃, —OCF₃,—OH, —OCH₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH, and —C(═O)OCH₃, whereinz is 0, 1, or 2. In one embodiment, each of R², R³, R⁴, and R⁵, if itdoes not join together with another of R² to R⁵ to form a ring, isindependently selected from the group consisting of H; methyl; ethyl;isopropyl; phenyl; cyclopropyl; —(CH₂)_(d)—NH_(2-z)(CH₃)_(z);—(CH₂)_(d)—O(CH₃); —CF₃; —OCF₃; —CH₂CF₃; —CH₂CHF₂; —CH₂CH₂F; halogen (inparticular, —F, —Cl, —Br); —CN; —NH₂; —NH(C₁₋₃ alkyl); —N(C₁₋₃ alkyl)₂;—C(═O)CH₃; —C(═O)CH₂NH_(2-z)(CH₃)_(z); —C(═O)O(C₁₋₃ alkyl);—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z); —NHC(═O)(C₁₋₃ alkyl); —S(O)₂(C₁₋₃alkyl); —S(O)₂(CH₂)_(d)NH_(2-z)(CH₃)_(z); —OH, and —O(C₁₋₃ alkyl),wherein z is 0, 1, or 2, d is 1, 2, or 3, and C₁₋₃ alkyl is methyl,ethyl, propyl or isopropyl. In one embodiment of the spiroquinoxalinederivative of formula (C-V), R¹, ring A, E, L and G are as defined above(in particular with respect to formulas (C-I), (C-II), (C-III), and(C-IV)) or below and R², R³, R⁴, and R⁵ are independently selected fromthe group consisting of —H, C₁₋₄ alkyl, and halogen, wherein the C₁₋₄alkyl is optionally substituted with 1, 2, or 3 independently selectedR³⁰ (in particular wherein R² and R⁵ are each —H). In one embodiment ofthe spiroquinoxaline derivative of formula (C-V), R¹, ring A, E, L and Gare as defined above (in particular with respect to formulas (C-I),(C-II), (C-III), and (C-IV)) or below and R², R³, R⁴, and R⁵ areindependently selected from the group consisting of —H, methyl, F, Cl,and CF₃ (in particular wherein R² and R⁵ are each —H). In one embodimentof the spiroquinoxaline derivative of formula (C-V), R¹, ring A, E, Land G are as defined above (in particular with respect to formulas(C-I), (C-II), (C-III), and (C-IV)) or below and R² and R⁵ are each —H;R³ is selected from the group consisting of —H, methyl, F, and Cl; andR⁴ is selected from the group consisting of —H, methyl, F, and Cl. Inone embodiment of the spiroquinoxaline derivative of formula (C-V), R¹,ring A, E, L and G are as defined above (in particular with respect toformulas (C-I), (C-II), (C-III), and (C-IV)) or below and (i) R² to R⁵are each —H; or (ii) R² and R⁵ are each —H, and both of R³ and R⁴ are F,Cl, or methyl.

In any of the above embodiments, wherein a ring is formed by (i) R² andR³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵, said ring preferably is a 3-to 7-membered ring (e.g., a ring having 5 or 6 members) which isoptionally substituted with one or more (such as 1 to the maximum numberof hydrogen atoms bound to the ring, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, orup to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2)independently selected R³⁰. The ring may be an aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N(R⁴⁰), wherein R⁴⁰ is selectedfrom the group consisting of R¹¹, —OR¹¹, —NH_(y)R²⁰ _(2-y), and—S(O)₁₋₂R¹¹, wherein R¹¹, R²⁰, and y are as defined above. In oneembodiment, the ring formed by (i) R² and R³, (ii) R³ and R⁴, and/or(iii) R⁴ and R⁵ is a 5- or 6-membered aromatic, cycloaliphatic,heteroaromatic, or heterocyclic ring, wherein theheteroaromatic/heterocyclic ring contains 1 or 2 heteroatoms selectedfrom the group consisting of O, S, and N, wherein at least oneheteroatom is N. In one embodiment, the ring formed by (i) R² and R³,(ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is selected from the groupconsisting of cyclopentadiene, furan, pyrrole, thiophene, imidazole,pyrazole, oxazole, isoxazole, thiazole, dioxole (e.g., 1,3-dioxole),benzene, pyridine, pyrazine, pyrimidine, pyridazine, dioxine (e.g.,1,4-dioxine), 1,2,3-triazine, 1,2,4-triazine, and di- or tetrahydroforms of each of the foregoing. In one embodiment, the ring formed (i)R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴ and R⁵ is cyclopentene (suchas 2,3-dihydrocyclopentadiene), dioxole (such as 1,3-dioxole, optionallysubstituted at position 2 with one or two halogen atoms (such as F)), ordioxine (such as 2,3-dihydro-[1,4]-dioxine). In one embodiment, thetotal number of rings formed by (i) R² and R³, (ii) R³ and R⁴, and/or(iii) R⁴ and R⁵ is 0 or 1. Thus, in the embodiment, wherein the totalnumber of rings formed by (i) R² and R³, (ii) R³ and R⁴, and/or (iii) R⁴and R⁵ is 1, only two adjacent substituents (i.e., either (i) R² and R³,(ii) R³ and R⁴, or (iii) R⁴ and R⁵) join together with the atoms towhich they are attached to form a ring, wherein the ring is as definedin any of the above embodiments and the remaining of R² to R⁵ areselected from the particular groups of moieties specified above for thesituation that they do not join together to form a ring. For example,the remaining R² to R⁵ which do not join together to form a ring may beselected from —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, 3- to 7-membered heterocyclyl, halogen, —CN, —OR¹¹,—N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —XC(═X)R¹¹, and—XC(═X)XR¹¹, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one or more (such as 1 to the maximum number ofhydrogen atoms bound to the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5-or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-memberedcycloalkyl, or 3- to 7-membered heterocyclyl group, e.g., 1, 2, 3, 4, 5,6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1or 2) independently selected R³⁰. In an alternative embodiment, R² to R⁵do not join together to form a ring.

In any of the above embodiments, R² and R⁵ may be the same and/or R³ andR⁴ may be the same.

In one embodiment of the spiroquinoxaline derivative of formula (C-V),R¹, ring A, E, L and G are as defined above (in particular with respectto formulas (C-I), (C-II), (C-III), and (C-IV)) or below and R², R³, R⁴,and R⁵ are independently selected from the group consisting of —H, C₁₋₄alkyl, and halogen, wherein the C₁₋₄ alkyl is optionally substitutedwith 1, 2, or 3 independently selected R³⁰ (in particular wherein R² andR⁵ are each —H), or R³ and R⁴ may join together with the atoms to whichthey are attached to form a 5- or 6-membered ring which is optionallysubstituted with one or two independently selected R³⁰. In oneembodiment of the spiroquinoxaline derivative of formula (C-V), R¹, ringA, E, L and G are as defined above (in particular with respect toformulas (C-I), (C-II), (C-III), and (C-IV)) or below and R², R³, R⁴,and R⁵ are independently selected from the group consisting of —H,methyl, F, Cl, and CF₃ (in particular wherein R² and R⁵ are each —H), orR³ and R⁴ may join together with the atoms to which they are attached toform a dioxole or dioxine ring which is optionally substituted with oneor two independently selected halogens (in particular F). In oneembodiment of the spiroquinoxaline derivative of formula (V), R¹, ringA, E, L and G are as defined above (in particular with respect toformulas (C-I), (C-II), (C-III), and (C-IV)) or below and R² and R⁵ areeach —H; R³ is selected from the group consisting of —H, methyl, F, andCl; and R⁴ is selected from the group consisting of —H, methyl, F, andCl; or R³ and R⁴ may join together with the atoms to which they areattached to form a dioxole (in particular 1,3-dioxole) or dioxine (inparticular 2,3-dihydro-[1,4]-dioxine) ring, wherein the dioxole ring isoptionally substituted with two F. In one embodiment of thespiroquinoxaline derivative of formula (C-V), R¹, ring A, E, L and G areas defined above (in particular with respect to formulas (C-I), (C-II),(C-III), and (C-IV)) or below and (i) R² to R⁵ are each —H; (ii) R² andR⁵ are each —H, and both of R³ and R⁴ are F, Cl, or methyl, or (iii) R²and R⁵ are each —H, and R³ and R⁴ join together with the atoms to whichthey are attached to form a 2,2-difluoro-1,3-dioxole ring or a2,3-dihydro-[1,4]-dioxine ring.

In any of the above embodiments (in particular with respect to formulas(C-I), (C-II), (C-III), (C-IV), and (C-V)), R³⁰, in each case, may be atypical 1^(st), 2^(nd), or 3^(rd) level substituent as specified aboveand may be independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5-, 6-, or7-membered heterocyclyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH,—C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃alkyl is methyl, ethyl, propyl or isopropyl, such as 4-morpholinyl,homomorpholinyl, 4-piperidinyl, homopiperidinyl (i.e., azepanyl, inparticular 4-azepanyl), 4-piperazinyl, homopiperazinyl (i.e.,diazepanyl, in particular 2,4-diazepanyl), N-methyl-piperazin-4-yl,N-methyl-homopiperazinyl, —CH₂CH₂OCH₃, —OCH₂CH₂OCH₃,—CH₂CH₂NH_(2-z)(CH₃)_(z), —OCH₂CH₂NH_(2-z)(CH₃)_(z), —CF₃, —OCF₃.Alternatively, R³⁰ may be selected from the group consisting of phenyl,furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, partially and completelyhydrogenated forms of the forgoing groups, morpholino, C₁₋₃ alkyl,halogen, —CF₃, —OH, —OCH₃, —OCF₃, —SCH₃, —NH_(2-z)(CH₃)_(z), —C(═O)OH,and —C(═O)OCH₃, wherein z is 0, 1, or 2.

In one embodiment, the compound of the invention is selected from thecompounds shown in Tables 1-N, 1-O/S, and 1-C.

It is intended that the compounds of the present invention (inparticular, the compounds of any one of formulas (I), (N-I), (O/S-I),(C-I), (II), (N-II), (O/S-II), (C-II), (III), (N-III), (O/S-III),(C-III), (IV), (N-IV), (O/S-IV), (C-IV), (V), (N-V), (O/S-V), and (C-V),such as those depicted in Tables 1-N, 1-O/S, and 1-C, below) encompassnot only the compounds as depicted but also their solvates (e.g.,hydrates), salts (in particular, pharmaceutically acceptable salts),complexes, polymorphs, crystalline forms, non-crystalline forms,amorphous forms, racemic mixtures, non-racemic mixtures, diastereomers,enantiomers, tautomers, unlabeled forms, isotopically labeled forms,prodrugs, and any combinations thereof.

A selection of compounds within the scope of, or for use within themethods of, the present invention is listed in the following Tables 1-N,1-O/S, and 1-C.

TABLE 1-N

N-1

N-2

N-3

N-4

N-5

N-6

N-7

N-8

N-9

N-10

N-11

N-12

N-13

N-14

N-15

N-16

N-17

N-18

N-19

N-20

N-21

N-22

N-23

N-24

N-25

N-26

N-27

N-28

N-29

N-30

N-31

N-32

N-33

N-34

N-35

N-36

N-37

N-38

N-39

N-40

N-41

N-42

N-43

N-44

N-45

N-46

N-47

N-48

N-49

N-50

N-51

N-52

N-53

N-54

N-55

N-56

N-57

N-58

N-59

N-60

N-61

N-62

N-63

N-64

N-65

N-66

N-67

N-68

N-69

N-70

N-71

N-72

N-73

N-74

N-75

N-76

N-77

N-78

N-79

N-80

N-81

N-82

N-83

N-84

N-85

N-86

N-87

N-88

N-89

N-90

N-91

N-92

N-93

N-94

N-95

N-96

N-97

N-98

N-99

N-100

N-101

N-102

N-103

N-104

N-105

N-106

N-107

N-108

N-109

N-110

N-111

N-112

N-113

N-114

N-115

N-116

N-117

N-118

N-119

N-120

N-121

N-122

N-123

N-124

N-125

N-126

N-127

N-128

N-129

N-130

N-131

N-132

N-133

N-134

N-135

N-136

N-137

N-138

N-139

N-140

N-141

N-142

N-143

N-144

N-145

N-146

N-147

N-148

N-149

N-150

N-151

N-152

N-153

N-154

N-156

N-155

N-157

N-158

N-159

N-160

N-161

N-162

N-163

N-164

N-165

N-166

N-167

N-168

N-169

N-170

N-171

N-172

N-173

N-174

N-175

N-176

N-177

N-178

N-179

N-180

N-181

N-182

N-183

N-184

N-185

N-186

N-187

N-188

N-189

N-190

N-191

N-192

N-193

N-194

N-195

N-196

N-197

N-198

N-199

N-200

N-201

N-202

N-203

N-204

N-205

N-206

N-207

N-208

N-209

N-210

N-211

N-212

N-213

N-214

N-215

N-216

N-217

N-218

N-219

N-220

N-221

N-222

N-223

N-224

N-225

N-226

N-227

N-228

N-229

N-230

N-231

N-232

N-233

N-234

N-235

N-236

N-237

N-238

N-239

N-240

N-241

N-242

N-243

N-244

N-245

N-246

N-247

N-248

N-249

N-250

N-251

N-252

N-253

N-254

N-255

N-256

N-257

N-258

N-259

N-260

N-261

N-262

TABLE 1-O/S

O/S-1

O/S-2

O/S-3

O/S-4

O/S-5

O/S-6

O/S-7

O/S-8

O/S-9

O/S-10

O/S-11

O/S-12

O/S-13

O/S-14

O/S-15

O/S-16

O/S-17

O/S-18

O/S-19

O/S-20

O/S-21

O/S-22

O/S-23

O/S-24

O/S-25

O/S-26

O/S-27

O/S-28

O/S-29

O/S-30

O/S-31

O/S-32

O/S-33

O/S-34

O/S-35

O/S-36

O/S-37

O/S-38

O/S-39

O/S-40

O/S-41

O/S-42

O/S-43

O/S-44

O/S-45

O/S-46

O/S-47

O/S-48

O/S-49

O/S-50

O/S-51

O/S-52

O/S-53

O/S-54

O/S-55

O/S-56

O/S-57

O/S-58

O/S-59

O/S-60

O/S-61

O/S-62

O/S-63

O/S-64

O/S-65

O/S-66

O/S-67

O/S-68

O/S-69

O/S-70

O/S-71

O/S-72

O/S-73

O/S-74

O/S-75

O/S-76

O/S-77

O/S-78

O/S-79

O/S-80

O/S-81

O/S-82

O/S-83

O/S-84

O/S-85

O/S-86

O/S-87

O/S-88

O/S-89

O/S-90

O/S-91

O/S-92

O/S-93

O/S-94

O/S-95

O/S-96

O/S-97

O/S-98

O/S-99

O/S-100

O/S-101

O/S-102

O/S-103

O/S-104

O/S-105

O/S-106

O/S-107

O/S-108

O/S-109

O/S-110

O/S-111

O/S-112

O/S-113

O/S-114

O/S-115

O/S-116

O/S-117

O/S-118

O/S-119

O/S-120

O/S-121

O/S-122

O/S-123

O/S-124

O/S-125

O/S-126

O/S-127

O/S-128

O/S-129

O/S-130

O/S-131

O/S-132

O/S-133

O/S-134

O/S-135

O/S-136

O/S-137

O/S-138

O/S-139

O/S-140

O/S-141

O/S-142

O/S-143

O/S-144

O/S-145

O/S-146

O/S-147

O/S-148

O/S-149

O/S-150

O/S-151

O/S-152

O/S-153

O/S-154

O/S-155

O/S-156

O/S-157

O/S-158

O/S-159

O/S-160

O/S-161

O/S-162

O/S-163

O/S-164

O/S-165

O/S-166

O/S-167

O/S-168

O/S-169

O/S-170

O/S-171

O/S-172

O/S-173

O/S-174

O/S-175

O/S-176

O/S-177

O/S-178

O/S-179

O/S-180

O/S-181

O/S-182

O/S-183

O/S-184

O/S-185

O/S-186

O/S-187

O/S-188

O/S-189

O/S-190

O/S-191

O/S-192

O/S-193

O/S-194

O/S-195

O/S-196

O/S-197

O/S-198

O/S-199

O/S-200

O/S-201

O/S-202

O/S-203

O/S-204

O/S-205

O/S-206

O/S-207

O/S-208

O/S-209

O/S-210

O/S-211

O/S-212

O/S-213

O/S-214

O/S-215

O/S-216

O/S-217

O/S-218

O/S-219

O/S-220

O/S-221

O/S-222

O/S-223

O/S-224

O/S-225

O/S-226

O/S-227

O/S-228

O/S-229

O/S-230

O/S-231

O/S-232

O/S-233

O/S-234

O/S-235

O/S-236

O/S-237

O/S-238

O/S-239

O/S-240

O/S-241

O/S-242

O/S-243

O/S-244

O/S-245

O/S-246

O/S-247

O/S-248

O/S-249

O/S-250

O/S-251

O/S-252

O/S-253

O/S-254

O/S-255

O/S-256

O/S-257

O/S-258

O/S-259

O/S-260

O/S-261

O/S-262

O/S-263

O/S-264

O/S-265

O/S-266

O/S-267

O/S-268

O/S-269

O/S-270

O/S-271

O/S-272

O/S-273

O/S-274

O/S-275

O/S-276

O/S-277

O/S-278

O/S-279

O/S-280

O/S-281

O/S-282

O/S-283

O/S-284

O/S-285

O/S-286

O/S-287

O/S-288

O/S-289

O/S-290

O/S-291

O/S-292

O/S-293

O/S-294

O/S-295

O/S-296

O/S-297

O/S-298

O/S-299

O/S-300

O/S-301

O/S-302

O/S-303

O/S-304

O/S-305

O/S-306

O/S-307

O/S-308

O/S-309

O/S-310

O/S-311

O/S-312

O/S-313

O/S-314

O/S-315

O/S-316

O/S-317

O/S-318

O/S-319

O/S-320

O/S-321

O/S-322

O/S-323

O/S-324

O/S-325

O/S-326

O/S-327

O/S-328

O/S-329

O/S-330

O/S-331

O/S-332

O/S-333

O/S-334

O/S-335

O/S-336

O/S-337

O/S-338

O/S-339

O/S-340

O/S-341

O/S-342

O/S-343

O/S-344

O/S-345

O/S-346

O/S-347

O/S-348

O/S-349

O/S-350

O/S-351

O/S-352

O/S-353

O/S-354

O/S-355

O/S-356

O/S-357

O/S-358

O/S-359

O/S-360

O/S-361

O/S-362

O/S-363

O/S-364

O/S-365

O/S-366

O/S-367

O/S-368

O/S-369

O/S-370

TABLE 1-C

C-1

C-2

C-3

C-4

C-5

C-6

C-7

C-8

C-9

C-10

C-11

C-12

C-13

C-14

C-15

C-16

C-17

C-18

C-19

C-20

C-21

C-22

C-23

C-24

C-25

C-26

C-27

C-28

C-29

C-30

C-31

C-32

C-33

C-34

C-35

C-36

C-37

C-38

C-39

C-40

C-41

C-42

C-43

C-44

C-45

C-46

C-47

C-48

C-49

C-50

C-51

C-52

C-53

C-54

C-55

C-56

C-57

C-58

C-59

C-60

C-61

C-62

C-63

C-64

C-65

C-66

C-67

C-68

C-69

C-70

C-71

C-72

C-73

C-74

C-75

C-76

C-77

C-78

C-79

C-80

C-81

C-82

C-83

C-84

C-85

C-86

C-87

C-88

C-89

C-90

C-91

C-92

C-93

C-94

C-95

C-96

C-97

C-98

C-99

C-100

C-101

C-102

C-103

C-104

C-105

C-106

C-107

C-108

C-109

C-110

C-111

C-112

C-113

C-114

C-115

C-116

C-117

C-118

C-119

C-120

C-121

C-122

C-123

C-124

C-125

C-126

C-127

C-128

C-129

C-130

C-131

C-132

C-133

C-134

C-135

C-136

C-137

C-138

C-139

C-140

C-141

C-142

C-143

C-144

C-145

C-146

C-147

C-148

C-149

C-150

C-151

C-152

C-153

C-154

C-155

C-156

C-157

C-158

C-159

C-160

C-161

C-162

C-163

C-164

C-165

C-166

C-167

C-168

C-169

C-170

C-171

C-172

C-173

C-174

C-175

C-176

C-177

C-178

C-179

C-180

C-181

C-182

C-183

C-184

C-185

C-186

C-187

C-188

C-189

C-190

C-191

C-192

C-193

C-194

C-195

C-196

C-197

C-198

C-199

C-200

C-201

C-202

C-203

C-204

C-205

C-206

C-207

C-208

C-209

C-210

C-211

C-212

C-213

C-214

C-215

C-216

C-217

C-218

C-219

C-220

C-221

C-222

C-223

C-224

C-225

C-226

C-227

C-228

C-229

C-230

C-231

C-232

C-233

C-234

C-235

C-236

C-237

C-238

C-239

C-240

C-241

C-242

C-243

C-244

C-245

C-246

C-247

C-248

C-249

C-250

C-251

C-252

C-253

C-254

C-255

C-256

C-257

C-258

C-259

C-260

C-261

C-262

C-263

C-264

C-265

C-266

C-267

C-268

C-269

In one embodiment, the compounds of the invention do not encompasscompounds of formula (I) wherein

(1) R² to R⁵ are each H, L is —CH₂—,

(i) G is unsubstituted phenyl, and ring A is

wherein R⁹ is —S(O)₂N(CH₃)₂, (cyclopropyl)sulfonyl, or(3-pyridinyl)sulfonyl, or R⁹ is —C(O)Z, wherein Z is methyl, tert-butyl,methoxymethyl, 2-methoxyethyl, —CH₂NHC(O)CH₃, 2-methoxyethylamino,morpholin-4-ylmethyl, 2-furanylmethylamino,(2-methyl-1H-imidazol-1-yl)methyl, 2-furanyl, 3-furanyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1-ethyl-1H-pyrazol-3-yl, or1-ethyl-1H-pyrazol-5-yl;(ii) G is unsubstituted phenyl, and ring A is

wherein R⁹ is (1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl or —C(O)Z,wherein Z is 2-methoxyethylamino, methoxycarbonylmethylamino,(2-trifluoromethylphenyl)amino, 5-chloro-1H-indol-2-yl,4,5,6,7-tetrahydro-1H-indazol-3-yl, or 3-(2-thienyl)-1H-pyrazol-5-yl;(iii) G is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-methoxyphenyl, or 4-methoxyphenyl, and ring A is

(iv) G is 3-methoxyphenyl, and ring A is

wherein R⁹ is (3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl;(v) G is 4-fluorophenyl, and ring A is

wherein R⁹ is —C(O)Z, wherein Z is 6-methoxy-1H-indol-2-yl or3,4-dimethoxyphenyl; or(vi) G is 4-chlorophenyl, and ring A is

wherein R⁹ is —C(O)Z, wherein Z is1-methyl-2-(2-methyl-1H-imidazol-1-yl)ethyl;(2) ring A is

R² and R⁵ are both H, L is —CH₂—, and(i) R³ and R⁴ are both H, and G is 3-methylphenyl, 3-methoxyphenyl,4-chlorophenyl, or 4-fluorophenyl; or(ii) R³ and R⁴ are both methyl, and G is 4-fluorophenyl; and/or(3) R² and R⁵ are both H, L is —CH₂—, and(i) R³ and R⁴ are both H, ring A is

and G is unsubstituted phenyl, 4-methylphenyl, 3-methoxyphenyl, or4-methoxyphenyl;(ii) R³ and R⁴ are both H, ring A is

and G is 4-methylphenyl, 4-fluorophenyl, 3,5-difluorophenyl, or3-methoxyphenyl;(iii) R³ and R⁴ are both H, ring A is

and G is unsubstituted phenyl, 3-methylphenyl, 4-fluorophenyl,2-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl,3,5-difluorophenyl, or 4-trifluoromethylphenyl;(iv) R³ and R⁴ are both H, ring A is

and G is 3-methoxyphenyl;(v) R³ and R⁴ are both H, ring A is

and G is unsubstituted phenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,3,5-difluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, or4-trifluoromethylphenyl;(vi) R³ and R⁴ are both methyl, ring A is

and G is 3-fluorophenyl or 3,5-difluorophenyl;(vii) R³ and R⁴ are both methyl, ring A is

and G is 3-fluorophenyl or 3-methoxyphenyl; or(viii) R³ and R⁴ are both methyl, ring A is

and G is unsubstituted phenyl, 2-methylphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, or 3-methoxyphenyl.

In one embodiment, the compounds of the invention have the generalformula (N-I) (such as (N-II), (N-III), (N-IV), or (N-V)) but do notencompass compounds of formula (N-I) wherein R² to R⁵ are each H, L is—CH₂—,

(i) G is unsubstituted phenyl, and ring A is

wherein R⁹ is —S(O)₂N(CH₃)₂, (cyclopropyl)sulfonyl, or(3-pyridinyl)sulfonyl, or R⁹ is —C(O)Z, wherein Z is methyl, tert-butyl,methoxymethyl, 2-methoxyethyl, —CH₂NHC(O)CH₃, 2-methoxyethylamino,morpholin-4-ylmethyl, 2-furanylmethylamino,(2-methyl-1H-imidazol-1-yl)methyl, 2-furanyl, 3-furanyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1-ethyl-1H-pyrazol-3-yl, or1-ethyl-1H-pyrazol-5-yl;(ii) G is unsubstituted phenyl, and ring A is

wherein R⁹ is (1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl or —C(O)Z,wherein Z is 2-methoxyethylamino, methoxycarbonylmethylamino,(2-trifluoromethylphenyl)amino, 5-chloro-1H-indol-2-yl,4,5,6,7-tetrahydro-1H-indazol-3-yl, or 3-(2-thienyl)-1H-pyrazol-5-yl;(iii) G is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-methoxyphenyl, or 4-methoxyphenyl, and ring A is

(iv) G is 3-methoxyphenyl, and ring A is

wherein R⁹ is (3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl;(v) G is 4-fluorophenyl, and ring A is

wherein R⁹ is —C(O)Z, wherein Z is 6-methoxy-1H-indol-2-yl or3,4-dimethoxyphenyl; or(vi) G is 4-chlorophenyl, and ring A is

wherein R⁹ is —C(O)Z, wherein Z is1-methyl-2-(2-methyl-1H-imidazol-1-yl)ethyl.

In one embodiment, the compounds of the invention have the generalformula (O/S-I) (such as (O/S-II), (O/S-III), (O/S-IV), or (O/S-V)) butdo not encompass compounds of formula (O/S-I) wherein ring A is

R² and R⁵ are both H, L is —CH₂—, and(i) R³ and R⁴ are both H, and G is 3-methylphenyl, 3-methoxyphenyl,4-chlorophenyl, or 4-fluorophenyl; or(ii) R³ and R⁴ are both methyl, and G is 4-fluorophenyl.

In one embodiment, the compounds of the invention have the generalformula (C-I) (such as (C-II), (C-III), (C-IV), or (C-V)) but do notencompass compounds of formula (C-I) wherein R² and R⁵ are both H, L is—CH₂—, and

(i) R³ and R⁴ are both H, ring A is

and G is unsubstituted phenyl, 4-methylphenyl, 3-methoxyphenyl, or4-methoxyphenyl;(ii) R³ and R⁴ are both H, ring A is

and G is 4-methylphenyl, 4-fluorophenyl, 3,5-difluorophenyl, or3-methoxyphenyl;(iii) R³ and R⁴ are both H, ring A is

and G is unsubstituted phenyl, 3-methylphenyl, 4-fluorophenyl,2-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl,3,5-difluorophenyl, or 4-trifluoromethylphenyl;(iv) R³ and R⁴ are both H, ring A is

and G is 3-methoxyphenyl;(v) R³ and R⁴ are both H, ring A is

and G is unsubstituted phenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,3,5-difluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, or4-trifluoromethylphenyl;(vi) R³ and R⁴ are both methyl, ring A is

and G is 3-fluorophenyl or 3,5-difluorophenyl;(vii) R³ and R⁴ are both methyl, ring A is

and G is 3-fluorophenyl or 3-methoxyphenyl; or(viii) R³ and R⁴ are both methyl, ring A is

and G is unsubstituted phenyl, 2-methylphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, or 3-methoxyphenyl.

The compounds of the invention which contain a basic functionality mayform salts with a variety of inorganic or organic acids. Exemplaryinorganic and organic acids/bases as well as exemplary acid/baseaddition salts of the compounds of the present invention are given inthe definition of “pharmaceutically acceptable salt” in the section“Pharmaceutical composition”, below. The compounds of the inventionwhich contain an acidic functionality may form salts with a variety ofinorganic or organic bases. The compounds of the invention which containboth basic and acidic functionalities may be converted into either baseor acid addition salt. The neutral forms of the compounds of theinvention may be regenerated by contacting the salt with a base or acidand isolating the parent compound in the conventional manner.

The compounds of the invention may be in a prodrug form. Prodrugs of thecompounds of the invention are those compounds that upon administrationto an individual undergo chemical conversion under physiologicalconditions to provide the compounds of the invention. Additionally,prodrugs can be converted to the compounds of the invention by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the compounds of the invention when, forexample, placed in a transdermal patch reservoir with a suitable enzymeor chemical reagent. Exemplary prodrugs are esters or amides which arehydrolyzable in vivo.

In a further aspect, the present invention provides a compound of theinvention (in particular those specified above with respect to any offormulas (I), (N-I), (O/S-I), (C-I), (II), (N-II), (O/S-II), (C-II),(III), (N-III), (O/S-III), (C-III), (IV), (N-IV), (O/S-IV), (C-IV), (V),(N-V), (O/S-V), and (C-V)) for use as medicament.

As it is evident from the examples, the inventors have found that thecompounds of the invention inhibit non-apoptotic regulated cell deathand/or reduce oxidative stress but do not inhibit apoptotic cell death.In one embodiment, the compounds of the invention are selectiveinhibitors of non-apoptotic regulated cell death and/or oxidativestress, i.e., they inhibit non-apoptotic regulated cell death and/oroxidative stress, but do not inhibit apoptotic cell death. In oneembodiment, the compounds of the invention exhibit pharmacologicalproperties (bioavailability, toxicity, side effects, dosing, patientcompliance, compatibility, stability, half-life, etc.), which are in atleast one aspect superior to the pharmacological properties exhibited byNecrostatin-1 and/or Ferrostatin.

Pharmaceutical Compositions

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound as specified above under the heading“Compounds” and one or more pharmaceutically acceptable excipients.

The pharmaceutical composition may be administered to an individual byany route, such as enterally or parenterally.

The compositions according to the present invention are generallyapplied in “pharmaceutically acceptable amounts” and in“pharmaceutically acceptable preparations”. Such compositions maycontain salts, buffers, preserving agents, carriers and optionally othertherapeutic agents. “Pharmaceutically acceptable salts” comprise, forexample, acid addition salts which may, for example, be formed by mixinga solution of compounds with a solution of a pharmaceutically acceptableacid such as hydrochloric acid, sulfuric acid, fumaric acid, maleicacid, succinic acid, acetic acid, benzoic acid, citric acid, tartaricacid, carbonic acid or phosphoric acid. Furthermore, where the compoundcarries an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include alkali metal salts (e.g., sodium or potassiumsalts); alkaline earth metal salts (e.g., calcium or magnesium salts);and salts formed with suitable organic ligands (e.g., ammonium,quaternary ammonium and amine cations formed using counteranions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkylsulfonate and aryl sulfonate). Illustrative examples of pharmaceuticallyacceptable salts include, but are not limited to, acetate, adipate,alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calciumedetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride,citrate, clavulanate, cyclopentanepropionate, digluconate,dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate,ethanesulfonate, formate, fumarate, galactate, galacturonate,gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate,glycolylarsanilate, hemisulfate, heptanoate, hexanoate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide,2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate,isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate,maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate,mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate,phosphate/diphosphate, phthalate, picrate, pivalate, polygalacturonate,propionate, salicylate, stearate, sulfate, suberate, succinate, tannate,tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, andthe like (see, for example, S. M. Berge et al., “Pharmaceutical Salts”,J. Pharm. Sci., 66, pp. 1-19 (1977)).

The term “excipient” when used herein is intended to indicate allsubstances in a pharmaceutical composition which are not activeingredients (e.g., which are therapeutically inactive ingredients thatdo not exhibit any therapeutic effect in the amount/concentration used),such as, e.g., carriers, binders, lubricants, thickeners, surface activeagents, preservatives, emulsifiers, buffers, flavoring agents,colorants, or antioxidants.

The compositions according to the present invention may comprise apharmaceutically acceptable carrier. As used herein, “pharmaceuticallyacceptable carrier” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, and the like that are physiologically compatible. The“pharmaceutically acceptable carrier” may be in the form of a solid,semisolid, liquid, or combinations thereof. Preferably, the carrier issuitable for enteral (such as oral) or parenteral administration (suchas intravenous, intramuscular, subcutaneous, spinal or epidermaladministration (e.g., by injection or infusion)). Depending on the routeof administration, the active compound, i.e., the compound of theinvention, may be coated in a material to protect the compound from theaction of acids and other natural conditions that may inactivate thecompound.

A composition of the present invention can be administered by a varietyof methods known in the art. As will be appreciated by the skilledartisan, the route and/or mode of administration will vary dependingupon the desired results. The active compounds can be prepared withcarriers that will protect the compound against rapid release, such as acontrolled release formulation, including implants, transdermal patches,and microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for the preparation of such formulations are generally known tothose skilled in the art. See, e.g., Sustained and Controlled ReleaseDrug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., NewYork, 1978.

To administer a compound of the invention by certain routes ofadministration, it may be necessary to coat the compound with, orco-administer the compound with, a material to prevent its inactivation.For example, the compound may be administered to an individual in anappropriate carrier, for example, liposomes, or a diluent.Pharmaceutically acceptable diluents include saline and aqueous buffersolutions. Liposomes include water-in-oil-in-water CGF emulsions as wellas conventional liposomes (Strejan et al., J. Neuroimmunol. 7: 27(1984)).

Pharmaceutically acceptable carriers include sterile aqueous solutionsor dispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersions. The use of such media andagents for pharmaceutically active substances is known in the art.Except insofar as any conventional media or agent is incompatible withthe active compound, use thereof in the pharmaceutical compositions ofthe invention is contemplated. Supplementary active compounds can alsobe incorporated into the compositions.

Pharmaceutical compositions typically must be sterile and stable underthe conditions of manufacture and storage. The composition can beformulated as a solution, microemulsion, liposome, or other orderedstructure suitable to high drug concentration. The carrier can be asolvent or dispersion medium containing, for example, water, ethanol,polyol (for example, glycerol, propylene glycol, and liquid polyethyleneglycol, and the like), and suitable mixtures thereof. The properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. In many cases, it will bepreferable to include isotonic agents, for example, sugars, polyalcoholssuch as mannitol, sorbitol, or sodium chloride in the composition.Prolonged absorption of the injectable compositions can be brought aboutby including in the composition an agent that delays absorption, forexample, monostearate salts and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed bysterilization microfiltration.

Generally, dispersions are prepared by incorporating the active compoundinto a sterile vehicle that contains a basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and freeze-drying(lyophilization) that yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Dosage regimens are adjusted to provide the optimum desired response(e.g., a therapeutic response). For example, a single bolus may beadministered, several divided doses may be administered over time or thedose may be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. It is especially advantageousto formulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suited as unitary dosages for theindividuals to be treated; each unit contains a predetermined quantityof active compound calculated to produce the desired therapeutic effectin association with the required pharmaceutical carrier. Thespecification for the dosage unit forms of the invention are dictated byand directly dependent on (a) the unique characteristics of the activecompound and the particular therapeutic effect to be achieved, and (b)the limitations inherent in the art of compounding such an activecompound for the treatment of sensitivity in individuals.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

For the therapeutic/pharmaceutical formulations, compositions of thepresent invention include those suitable for enteral administration(such as oral or rectal) or parenteral administration (such as nasal,topical (including vaginal, buccal and sublingual)). The compositionsmay conveniently be presented in unit dosage form and may be prepared byany methods known in the art of pharmacy. The amount of activeingredient (in particular, the amount of a compound of the presentinvention) which can be combined with a carrier material to produce apharmaceutical composition (such as a single dosage form) will varydepending upon the individual being treated, and the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the composition which produces a therapeutic effect.

Generally, out of 100% (for the pharmaceuticalformulations/compositions), the amount of active ingredient (inparticular, the amount of the compound of the present invention,optionally together with other therapeutically active agents, if presentin the pharmaceutical formulations/compositions) will range from about0.01% to about 99%, preferably from about 0.1% to about 70%, mostpreferably from about 1% to about 30%, wherein the reminder ispreferably composed of the one or more pharmaceutically acceptableexcipients.

The amount of active ingredient, e.g., a compound of the invention, in aunit dosage form and/or when administered to an individual or used intherapy, may range from about 0.1 mg to about 1000 mg (for example, fromabout 1 mg to about 500 mg, such as from about 10 mg to about 200 mg)per unit, administration or therapy. In certain embodiments, a suitableamount of such active ingredient may be calculated using the mass orbody surface area of the individual, including amounts of between about1 mg/Kg and 10 mg/Kg (such as between about 2 mg/Kg and 5 mg/Kg), orbetween about 1 mg/m² and about 400 mg/m² (such as between about 3 mg/m²and about 350 mg/m² or between about 10 mg/m² and about 200 mg/m²).

Compositions of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate. Dosage forms for the topical or transdermaladministration of compositions of this invention include powders,sprays, ointments, pastes, creams, lotions, gels, solutions, patches andinhalants. The active compound may be mixed under sterile conditionswith a pharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants which may be required.

The expressions “enteral administration” and “administered enterally” asused herein mean that the drug administered is taken up by the stomachand/or the intestine. Examples of enteral administration include oraland rectal administration. The expressions “parenteral administration”and “administered parenterally” as used herein mean modes ofadministration other than enteral administration, usually by injectionor topical application, and include, without limitation, intravenous,intramuscular, intraarterial, intrathecal, intracapsular, intraosseous,intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intraarticular, subcapsular, intracerebral,intracerebroventricular, subarachnoid, intraspinal, epidural andintrasternal administration (such as by injection and/or infusion) aswell as topical administration (e.g., epicutaneous, inhalational, orthrough mucous membranes (such as buccal, sublingual or vaginal)).

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents, pH buffering agents, and dispersingagents. Prevention of the presence of microorganisms may be ensured bothby sterilization procedures, and by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art (cf., e.g., Remington, “The Scienceand Practice of Pharmacy” edited by Allen, Loyd V., Jr., 22^(nd)edition, Pharmaceutical Sciences, September 2012; Ansel et al.,“Pharmaceutical Dosage Forms and Drug Delivery Systems”, 7^(th) edition,Lippincott Williams & Wilkins Publishers, 1999.).

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of the present invention may be varied so as to obtain anamount of the active ingredient which is effective to achieve thedesired therapeutic response for a particular patient, composition, andmode of administration, without being toxic to the patient. The selecteddosage level will depend upon a variety of pharmacokinetic factorsincluding the activity of the particular compositions of the presentinvention employed, the route of administration, the time ofadministration, the rate of excretion of the particular compound beingemployed, the duration of the treatment, other drugs, compounds and/ormaterials used in combination with the particular compositions employed,the age, sex, weight, condition, general health and prior medicalhistory of the patient being treated, and like factors well known in themedical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart with doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved. In general, a suitabledaily dose of a composition of the invention will be that amount of thecompound which is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above. It is preferred that administration be oral,intravenous, intramuscular, intraperitoneal, or subcutaneous, preferablyadministered proximal to the site of the target. If desired, theeffective daily dose of a pharmaceutical composition may be administeredas two, three, four, five, six or more sub-doses administered separatelyat appropriate intervals throughout the day, optionally, in unit dosageforms. While it is possible for a compound of the present invention tobe administered alone, it is preferable to administer the compound as apharmaceutical formulation/composition.

In one embodiment, the compounds or compositions of the invention may beadministered by infusion, preferably slow continuous infusion over along period, such as more than 24 hours, in order to reduce toxic sideeffects. The administration may also be performed by continuous infusionover a period of from 2 to 24 hours, such as of from 2 to 12 hours. Suchregimen may be repeated one or more times as necessary, for example,after 6 months or 12 months.

In yet another embodiment, the compounds or compositions of theinvention are administered by maintenance therapy, such as, e.g., once aweek for a period of 6 months or more.

For oral administration, the pharmaceutical composition of the inventioncan take the form of, for example, tablets or capsules prepared byconventional means with pharmaceutical acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone,hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystallinecellulose, calcium hydrogen phosphate), lubricants (e.g., magnesiumstearate, talc, silica), disintegrants (e.g., potato starch, sodiumstarch glycolate), or wetting agents (e.g., sodium lauryl sulphate).Liquid preparations for oral administration can be in the form of, forexample, solutions, syrups, or suspensions, or can be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparation can be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol, syrup, cellulose derivatives, hydrogenated edible fats),emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g.,almond oil, oily esters, ethyl alcohol, fractionated vegetable oils),preservatives (e.g., methyl or propyl-p-hydroxycarbonates, sorbicacids). The preparations can also contain buffer salts, flavouring,coloring and sweetening agents as deemed appropriate. Preparations fororal administration can be suitably formulated to give controlledrelease of the pharmaceutical composition of the invention.

The pharmaceutical composition can be formulated as a suppository, withtraditional binders and carriers such as triglycerides. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc.

For administration by inhalation, the pharmaceutical composition of theinvention is conveniently delivered in the form of an aerosol spraypresentation from a pressurised pack or a nebulizer, with the use of asuitable propellant (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide,nitrogen, or other suitable gas). In the case of a pressurised aerosol,the dosage unit can be determined by providing a valve to deliver ametered amount. Capsules and cartridges of, for example, gelatine, foruse in an inhaler or insufflator can be formulated containing a powdermix of the pharmaceutical composition of the invention and a suitablepowder base such as lactose or starch.

The pharmaceutical composition of the invention can be formulated forparenteral administration by injection, for example, by bolus injectionor continuous infusion. Formulations for injection can be presented inunits dosage form (e.g., in phial, in multi-dose container), and with anadded preservative. The pharmaceutical composition of the invention cantake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and can contain formulatory agents such as suspending,stabilizing, or dispersing agents. Alternatively, the agent can be inpowder form for constitution with a suitable vehicle (e.g., sterilepyrogen-free water) before use. Typically, compositions for intravenousadministration are solutions in sterile isotonic aqueous buffer. Wherenecessary, the composition can also include a solubilizing agent and alocal anesthetic such as lignocaine to ease pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilisedpowder or water free concentrate in a hermetically sealed container suchas an ampoule or sachette indicating the quantity of active agent. Wherethe composition is to be administered by infusion, it can be dispensedwith an infusion bottle containing sterile pharmaceutical grade water orsaline. Where the composition is administered by injection, an ampouleof sterile water for injection or saline can be provided so that theingredients can be mixed prior to administration.

Therapeutic/pharmaceutical compositions can be administered with medicaldevices known in the art. For example, in a preferred embodiment, atherapeutic/pharmaceutical composition of the invention can beadministered with a needleless hypodermic injection device, such as thedevices disclosed in U.S. Pat. No. 5,399,163; 5,383,851; 5,312,335;5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-knownimplants and modules useful in the present invention include thosedescribed in: U.S. Pat. No. 4,487,603, which discloses an implantablemicro-infusion pump for dispensing medication at a controlled rate; U.S.Pat. No. 4,486,194, which discloses a therapeutic device foradministering medicants through the skin; U.S. Pat. No. 4,447,233, whichdiscloses a medication infusion pump for delivering medication at aprecise infusion rate; U.S. Pat. No. 4,447,224, which discloses avariable flow implantable infusion apparatus for continuous drugdelivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drugdelivery system having multi-chamber compartments; and U.S. Pat. No.4,475,196, which discloses an osmotic drug delivery system.

Many other such implants, delivery systems, and modules are known tothose skilled in the art. In certain embodiments, the compounds of theinvention can be formulated to ensure proper distribution in vivo. Forexample, the blood-brain barrier (BBB) excludes many highly hydrophiliccompounds. To ensure that the compounds of the invention cross the BBB(if desired), they can be formulated, for example, in liposomes. Formethods of manufacturing liposomes, see, e.g., U.S. Pat. Nos. 4,522,811;5,374,548; and 5,399,331. The liposomes may comprise one or moremoieties which are selectively transported into specific cells ororgans, and thus enhance targeted drug delivery (see, e.g., V. V. Ranade(1989) J. Clin. Pharmacol. 29: 685). Exemplary targeting moietiesinclude folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low etal.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun.153: 1038); antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357: 140;M. Owais et al. (1995) Antimicrob. Agents Chemother. 39: 180); andsurfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol.1233: 134).

In one embodiment of the invention, the compounds of the invention areformulated in liposomes. In a more preferred embodiment, the liposomesinclude a targeting moiety. In a most preferred embodiment, thecompounds in the liposomes are delivered by bolus injection to a siteproximal to the desired area. Such liposome-based composition should befluid to the extent that easy syringability exists, should be stableunder the conditions of manufacture and storage and should be preservedagainst the contaminating action of microorganisms such as bacteria andfungi.

A “therapeutically effective dosage” for therapy/treatment can bemeasured by objective responses which can either be complete or partial.A complete response (CR) is defined as no clinical, radiological orother evidence of a condition, disorder or disease. A partial response(PR) results from a reduction in disease of greater than 50%. Mediantime to progression is a measure that characterizes the durability ofthe objective response.

A “therapeutically effective dosage” for therapy/treatment can also bemeasured by its ability to stabilize the progression of a condition,disorder or disease. The ability of a compound to inhibit, reduce orameliorate non-apoptotic regulated cell-death and/or to reduce oxidativestress can be evaluated in appropriate animal model systems as such asone or more of those set fourth below. Alternatively, these propertiesof a compound of the present invention can be evaluated by examining theability of the compound using in vitro assays known to the skilledpractitioner such as one or more of those set fourth below. Atherapeutically effective amount of a compound of the present inventioncan cure, heal, alleviate, relieve, alter, remedy, ameliorate, improveor affect the condition, disorder or disease or the symptoms of thecondition, disorder or disease or the predisposition toward thecondition, disorder or disease in an individual. One of ordinary skillin the art would be able to determine such amounts based on such factorsas the individual's size, the severity of the individual's symptoms, andthe particular composition or route of administration selected.

An injectable composition should be sterile and fluid to the extent thatthe composition is deliverable by syringe. In addition to water, thecarrier can be an isotonic buffered saline solution, ethanol, polyol(for example, glycerol, propylene glycol, and liquid polyethyleneglycol, and the like), and suitable mixtures thereof.

The pharmaceutical composition of the invention can also, if desired, bepresented in a pack, or dispenser device which can contain one or moreunit dosage forms containing the said agent. The pack can for examplecomprise metal or plastic foil, such as blister pack. The pack ordispenser device can be accompanied with instruction for administration.

The pharmaceutical composition of the invention can be administered assole active agent or can be administered in combination with othertherapeutically and/or cosmetically active agents.

Therapeutic and Other Applications

In further aspects, the present application provides a compound asspecified above under the heading “Compounds” or a pharmaceuticalcomposition as specified above under the heading “Pharmaceuticalcompositions” for use in therapy.

It is contemplated that the compound as specified above under theheading “Compounds” may be used for the inhibition, reduction oramelioration of non-apoptotic regulated cell death and/or the reductionof oxidative stress in vitro, such as in an isolated cell, an isolatedcell culture, or a sample, tissue or organ isolated from an individual.In certain embodiments, such cell, cell culture, sample, tissue or organis used in research; while in other embodiments it is exposed to thecompound ex-vivo prior to reintroduction to the same (or a different)individual, such as in tissue or organ transplant, and the inhibition,reduction or amelioration of regulated necrosis of such cell, cellculture, sample, tissue or organ takes place when ex-vivo.

The compounds and/or pharmaceutical compositions of the invention may beused in the treatment (including prophylactic treatment) of a condition,disorder or disease:

-   -   that is characterised by non-apoptotic regulated cell-death        (including regulated necrosis, necroptosis or ferroptosis), or        where non-apoptotic regulated cell-death is likely to play or        plays a substantial role;    -   that is characterised by oxidative stress (including increased        level of reactive oxygen species (ROS)), or where oxidative        stress is likely to play or plays a substantial role; and/or    -   that is characterised by activation of:        -   one or more components of the necrosome such as RIP1 and/or            RIP3;        -   Death domain receptors such as TNFR1, TNFR2, Fas/CD95 and/or            TRAIL-R; and/or        -   Toll-like receptors such as TLR3 and/or TLR4,            or where activation of any of the foregoing component            and/ort receptor is likely to play or plays a substantial            role.

The compounds and/or pharmaceutical compositions of the invention may beused in the treatment (including prophylactic treatment) of a condition,disorder or disease that is selected from the group consisting of:

-   -   a neurodegenerative disease of the central or peripheral nervous        system, a condition or disorder caused by and forms of        neurodegeneration;    -   muscle wasting or muscular dystrophy; organ ischemia (e.g.,        stroke, myocardial infarction and heart, mesenteric, retinal,        hepatic or brain ischemic injury), ischemic-reperfusion injury        (such as associated with surgery, especially solid organ        transplantation), ischemic injury during organ storage, limb or        organ ischemic injury (such as associated with surgery,        tourniquet use or trauma);    -   compartment syndrome, gangrene, pressure sores, sepsis (e.g.,        aseptic necrosis), degenerative arthritis;    -   retinal necrosis (e.g., acute retinal necrosis (ARN) cased by or        associated with optic nerve detachment);    -   cardiovascular (heart) disease, including stroke, coronary heart        disease, cardiomyopathy;    -   liver, gastrointestinal or pancreatic disease (e.g., acute        necrotizing pancreatitis);    -   avascular necrosis (e.g., bone avascular necrosis), diabetes,        sickle cell disease, alteration of blood vessels (e.g., vascular        dystrophy or cerebrovascular disease);    -   cancer-chemo/radiation therapy-induced cell-death (e.g.,        mucositis or chemotherapy induced alopecia (CIA)); and    -   cell, tissue, organ or organism intoxication (e.g.,        nephrotoxicity), such as that the result of, arising from or        associated with drug treatment (e.g., complications from steroid        treatment, kidney toxicity from cisplatin, cardiotoxicity from        doxorubicin or ototoxicity from gentamicin), drug overdose        (e.g., liver toxicity from paracetamol) or acute poisoning        (e.g., from alcohol, paraquat or environmental toxins), or        contrast-agent-induced toxicity; and    -   priapism;        or is the result of, arises from or is associated with any of        the foregoing.

The compounds and/or pharmaceutical compositions of the invention may beused in the treatment (including prophylactic treatment) of a condition,disorder or disease that is the result of, arises from or is associatedwith a circumstance selected from the group consisting of:

-   -   forms of infection of viruses, bacteria, fungi or other        microorganisms (eg, septic shock, tuberculosis);    -   a reduction in cell-proliferation, or an alteration in        cell-differentiation or intracellular signalling;    -   an undesirable inflammation, such as an immune disorder;    -   retinal neuronal cell death, cell death of cardiac muscle, cell        death of cells of the immune system, cell death associated with        renal failure;    -   neonatal respiratory distress, asphyxia, incarcerated hernia,        placental infarct, iron-load complications, endometriosis,        congenital disease, including congenital mitochondrial disease        (eg, tyrosinemia, phenylketonuria, Anderson disease);    -   head trauma/traumatic brain injury, liver injury;    -   injuries from environmental radiation (e.g., UV exposure and        sunburn);    -   burns;    -   cold injuries (e.g., hyperthermia), mechanical injuries (e.g.,        brain and spinal cord injuries); and    -   decompression sickness;    -   snake, scorpion or spider bites; and    -   side effects of medications.

In certain of such embodiments, the condition, disorder or disease isnot cancer, and/or is not one the result of, arising from or associatedwith cancer.

Without being bound by theory, apoptosis (e.g., as assays in ExampleB.3) is believed to occur under or as a result of normal physiologicalconditions or events in a highly programmed manner as part of normaltissue homeostasis and cell turnover; while, conversely, non-apoptoticregulated cell death is thought to be triggered by abnormalphysiological conditions or events such as external damaging stimuliand/or oxidative stress. Compounds that inhibit non-apoptotic regulatedcell-death but do not appear to inhibit apoptotic cell-death may havepreferred utility in the methods and applications of the presentinvention, as they may not interfere with the individual's (such) innatecell-death mechanism and regulation, but preferentially only that causedby abnormal physiological conditions or events such as external damagingstimuli and/or oxidative stress and/or triggering events of the immunesystem.

In particular embodiments, the condition, disorder or disease is aneurodegenerative disease, including of either or both of the central orperipheral nervous systems, or is a condition or disorder caused by andforms of neurodegeneration, or is a condition or symptom the result of,arising from or associated with such condition, disorder or disease.

Exemplary neurodegenerative such conditions or diseases include, but arenot limited to, Alzheimer's disease, Huntington's disease, Parkinson'sdisease, amyotrophic lateral sclerosis (ALS), HIV-associated dementia,cerebral ischemia, multiple sclerosis, Lewy body disease, Menke'sdisease, Wilson's disease, Creutzfeldt-Jakob disease, Fahr disease, andfrontotemporal dementia, amyloidosis, Tay-Sachs disease andperiventricular leukomalacia.

In some of such embodiments, the condition, disorder or disease ismuscle wasting (eg, that associated with cancer, AIDS, congestive heartfailure, chronic obstructive disease, and necrotizing myopathy ofintensive care). In particular embodiments the condition, disorder ordisease is muscular dystrophies or related diseases (e.g., Becker'smuscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy,limb-girdle muscular dystrophy, Landouzy-Dejerine muscular dystrophy,facioscapulohumeral muscular dystrophy (Steinert's disease), myotoniacongenita, Thomsen's disease, and Pompe's disease), or is a condition orsymptom the result of, arising from or associated with such condition,disorder or disease.

In other embodiments, the condition, disorder or disease is cell,tissue, organ or organism intoxication, such as that the result of,arising from or associated with drug treatment, drug overdose or acutepoisoning. Exemplary circumstances of such intoxication includealcoholism and administration and/or self-administration with, and/orexposure to, illicit drugs (e.g., cocaine, heroin, crack), medical drugs(e.g., anti-cancer agents, paracetamol, antibiotics, adriamycin, NSAID,cyclosporine), chemical toxins (e.g., carbon tetrachloride, cyanide,methanol, ethylene glycol and mustard gas, agrochemicals such asorganophosphates and paraquat, and warfare organophosphates), or heavymetals (e.g., lead, mercury).

In other particular embodiments, the condition, disorder or disease isthe result of, arising from or associated with one or more forms ofinfection of viruses (e.g., acute, latent and/or persistent), bacteria,fungi, or other microorganisms, or is one in which a reduction incell-proliferation, or an alteration in cell-differentiation orintracellular signalling, is a causative factor, and include infectione.g., by viruses (e.g., acute, latent and/or persistent), bacteria,fungi, or other microorganisms, and mycoplasma disease.

Exemplary viruses include, but are not limited to, are humanimmunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus(CMV) (e.g., CMV5), human herpesviruses (HHV) (e.g., HHV6, 7 or 8),herpes simplex viruses (HSV), bovine herpes virus (BHV) (e.g., BHV4),equine herpes virus (EHV) (e.g., EHV2), human T-Cell leukemia viruses(HTLV)5, Varicella-Zoster virus (VZV), measles virus, papovaviruses (JCand BK), hepatitis viruses (E.g., HBV or HCV), myxoma virus, adenovirus,parvoviruses, polyoma virus, influenza viruses, papillomaviruses andpoxviruses such as vaccinia virus, and molluscum contagiosum virus(MCV), and lyssaviruses. Such virus may or may not express an apoptosisinhibitor. Exemplary diseases caused by viral infection include, but arenot limited to, chicken pox, Cytomegalovirus infections, genital herpes,Hepatitis B and C, influenza, and shingles, and rabies.

Exemplary bacteria include, but are not limited to, Campylobacterjejuni, Enterobacter species, Enterococcus faecium, Enterococcusfaecalis, Escherichia coli (e.g., F. coli O157:H7), Group Astreptococci, Haemophilus influenzae, Helicobacter pylori, listeria,Mycobacterium tuberculosis, Pseudomonas aeruginosa, S. pneumoniae,Salmonella, Shigella, Staphylococcus aureus, and Staphylococcusepidermidis, and Borrelia and Rickettsia. Exemplary diseases caused bybacterial infection include, but are not limited to, anthrax, cholera,diphtheria, foodborne illnesses, leprosy, meningitis, peptic ulcerdisease, pneumonia, sepsis, septic shock, syphilis, tetanus,tuberculosis, typhoid fever, and urinary tract infection, and Lymedisease and Rocky Mountain spotted fever.

In further particular embodiments, the condition, disorder or disease isthe result of, arising from or associated with undesirable inflammation,such as an immune disorder.

Exemplary immune disorders include, but are not limited to, autoimmunediseases (for example, diabetes mellitus, arthritis—including rheumatoidarthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriaticarthritis —, multiple sclerosis, encephalomyelitis, myasthenia gravis,systemic lupus erythematosis, autoimmune thyroiditis, dermatitis(including atopic dermatitis and eczematous dermatitis), psoriasis,Sjogren's Syndrome, Crohn's disease, aphthous ulcer, iritis,conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma,allergic asthma, sepsis and septic shock, inflammatory bowel disorder,cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drugeruptions, leprosy reversal reactions, erythema nodosum leprosum,autoimmune uveitis, allergic encephalomyelitis, acute necrotizinghemorrhagic encephalopathy, idiopathic bilateral progressivesensorineural hearing loss, aplastic anemia, pure red cell anemia,idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis,chronic active hepatitis, Stevens-Johnson syndrome, glomerulonephritis,idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primarybiliary cirrhosis, uveitis posterior, and interstitial lung fibrosis),graft-versus-host disease, cases of transplantation, and allergy suchas, atopic allergy.

Compounds and methods of the invention can additionally be used to boostthe immune system, whether or not the patient being treated has animmunocompromising condition. For example, the compounds describedherein can be used in a method to strengthen the immune system duringimmunisation, e.g., by functioning as an adjuvant, or by being combinedwith an adjuvant.

Ischemia-reperfusion injury (IRI) remains a primary complication oftransplant surgery, accounting for the majority of liver transplantfailures, with non-apoptotic regulated cell death believed to be a maincontributor to IRI. In contrast to apoptosis where cell death is limitedto the affected cell, non-apoptotic regulated cell death, such asregulated necrosis, may cause inflammatory conditions damagingsurrounding tissue. Compounds of the inventions that reduce IRI damagein the liver can be proposed as drug-candidates and have utility asmedicines for limiting organ trauma upon transplantation and otherdiseases or conditions caused by ischemia-reperfusion and such utilitycan be tested in an in vivo model, for example, as described by Abe etal. (Free Radic. Biol. Med. 46: 1-7 (2009)).

Ischemia-reperfusion injury remains a primary complication of transplantsurgery, accounting for the majority of kidney transplant failures,acute kidney tubular necrosis and delayed graft function. Compounds ofthe invention that reduce IRI damage in the kidney can be proposed asdrug-candidates and have utility as medicines for limiting organ traumaupon transplantation and other diseases or conditions caused byischemia-reperfusion, and such utility can be tested in an in vivomodel, for example, as described by Wu et al. (J. Clin. Invest.117:2847-59 (2007)) and Linkermann et al. (Kidney Int. 81: 751-761(2012)).

Overdose of APAP is the most common cause of drug-induced liver damage,morbidity and mortality in humans in the United States, Great Britain,and other parts of the world. Metabolic bioactivation of APAP to thereactive electrophile N-acetyl-p-benzoquinone imine (NAPQI) causesextensive and rapid glutathione (GSH) depletion, and ultimately,hepatotoxicity. At present, N-acetylcysteine (NAC) is the antidote ofchoice for acetaminophen overdoses, although it is only protective forthe injured liver when administered shortly after intoxication of anAPAP overdose. Compounds of the invention that inhibit non-apoptoticregulated cell-death can be proposed as drug-candidates and have utilityas medicines for limiting the effects of APA intoxication, and suchutility can be tested in an in vivo model, for example, as described byPatterson et al. (Chem. Res. Toxicol. 26:1088-96 (2013)).

Cisplatin is a widely used and potent chemotherapeutic agent to treat awide spectrum of mainly solid malignancies. Upon entering cells, thechloride atoms in cisplatin are replaced by H₂O. The hydrolysis productis a reactive molecule that reacts with DNA, but also with GSH. Thesecisplatin-DNA intra-strand crosslinks result in cytotoxicity towardstumour cells, however, side-reactions with GSH mediate toxic effectssuch as nephrotoxicity, which in fact is the dose-limiting side effect.GSH depletion and concomitant cell death injure primarily the S3 segmentof the proximal tubule in kidney and lead to renal failure (renaltubular dysfunction). Compounds of the invention that inhibitnon-apoptotic regulated cell-death can be proposed as drug-candidatesand have utility as medicines for limiting the effects of cisplatinintoxication, and such utility can be tested in an in vivo model, forexample, as described by Tristao et al. (Ren. Fail. 34:373-7 (2012)).

Non-apoptotic regulated cell death plays a major role in thepathogenesis of traumatic brain injury (TBI), and the utility ofcompounds of the invention as a medicine for suchcondition/disorder/disease can be investigated using an in-vivo murinemodel for example as described by You et al. (J. Cereb. Blood FlowMetab. 28:1564-73 (2008)), or Rauen et al. (J. Neurotrauma 30:1442-8(2013)).

TNF-alpha overproduction and increased ROS levels are major contributorsto RA. The collagen-induced arthritis (CIA) mouse model is the mostcommonly studied autoimmune model of rheumatoid arthritis, for exampleas described by Brand et al. (Nat. Protoc. 2:1269-75 (2007)), and can beused to study the utility of compounds of the invention to treat RA.

Oxidative stress plays a major role in the pathogenesis of multiplesclerosis (MS). Reactive oxygen species (ROS) have been implicated asmediators of demyelination and axonal damage in both MS and its animalmodel, experimental autoimmune encephalomyelitis (EAE). Experimentalautoimmune encephalomyelitis (EAE) is the most commonly usedexperimental model for the human inflammatory demyelinating disease,multiple sclerosis (MS), for example as described by Racke (Curr.Protoc. Neurosci. 9:unit 9.7 (2001)), and can be used to study theutility of compounds of the invention to treat MS.

Septic shock is linked to GSH depletion and multi-organ failure.Children, immune-compromised individuals and elderly people are mostaffected. Septic shock patients are cared for in intensive care unitsand the mortality rate is a shocking 25-50%. The disease is caused bygram-negative bacteria that produce endotoxins, also known as bacterialwall lipopolysaccharides. LPS is well known for its ability to triggeroxidative stress and activate the innate immune response by inducing theCD14/TLR4/MD2 receptor complex. This in turn leads to the secretion ofpro-inflammatory cytokines in many cell types, particularly in B cellsand macrophages. Compounds of the invention that inhibit non-apoptoticregulated cell-death can be proposed as drug-candidates and have utilityas medicines for limiting the effects of LPS-induced endotoxic shock,and this utility can be investigated using an in-vivo murine model forexample as described by Duprez et al. (Immunity 35:908-18 (2011)).

The compounds of the invention may be used for treatment alone or inconjunction with one or more other therapeutically active agents, forexample in combination with apoptosis inhibitors.

Treatment including the compounds of the invention may be provided athome, the doctor's office, a clinic, a hospital's outpatient department,or a hospital. Treatment generally begins under medical supervision sothat medical personnel can observe the treatment's effects closely andmake any adjustments that are needed. The duration of the treatmentdepends on the age and condition of the patient, as well as how thepatient responds to the treatment.

A person having a greater risk of developing a condition, disorder ordisease may receive prophylactic treatment to inhibit or delay symptomsof the condition, disorder or disease.

The term “treatment” is known to the person of ordinary skill, andincludes the application or administration of an agent (e.g., apharmaceutical composition containing said agent) or procedure to apatient or application or administration of an agent (e.g., apharmaceutical composition containing said agent) or procedure to acell, cell culture, cell line, sample, tissue or organ isolated from apatient, who has a condition, disorder or disease, a symptom of thecondition, disorder or disease or a predisposition toward a condition,disorder or disease, with the purpose to cure, heal, alleviate, relieve,alter, remedy, ameliorate, improve, affect or prevent the condition,disorder or disease, the symptoms of the condition, disorder or diseaseor the predisposition toward the condition, disorder or disease. Hence,the term “treatment” can include prophylactic treatment of a condition,disorder or disease, or the symptom of a condition, disorder or disease.An agent, when used in treatment, includes the compounds describedherein and includes, but is not limited to, other therapeutically activeagents that may be small molecules, peptides, peptidomimetics,polypeptides/proteins, antibodies, nucleotides such as DNA or RNA,cells, viruses, ribozymes, siRNA, and antisense oligonucleotides

In an alternative aspect, the compounds of the present invention may beevaluated for their pharmacological properties in animal models ofdisease. The compounds identified to decrease non-apoptotic regulatedcell-death may be structurally modified and subsequently used todecrease non-apoptotic regulated cell-death, or in treatment (includingprophylactic treatment) of a condition, disorder or disease as describedherein. The methods used to generate structural derivatives of the smallmolecules that decrease non-apoptotic regulated cell-death are readilyknown to those skilled in the fields of organic and medicinal chemistry.

Also in an alternative aspect, the compounds of the invention may beused in the cosmetic treatment (including prophylactic and cosmetictreatment) of an aesthetic feature associated with UV-damage in skin,ageing in skin, and/or hair loss.

Also, in an additional alternative aspect, the invention relates to astorage solution for organ transport and/or transplant comprising acompound of the invention.

The inventors have identified the compounds of the present invention asa class of small molecules that effectively and selectively inhibitnon-apoptotic regulated cell death and/or reduce oxidative stress but donot inhibit apoptotic cell death.

Thus, the present invention provides (i) a compound of the invention (ora pharmaceutical composition comprising such compound optionallytogether with a pharmaceutically acceptable excipient) for use in amethod of treating (a) a condition, disorder or disease that ischaracterised by non-apoptotic regulated cell-death or wherenon-apoptotic regulated cell-death is likely to play or plays asubstantial role; (b) a condition, disorder or disease that ischaracterised by oxidative stress or where oxidative stress is likely toplay or plays a substantial role; and/or (c) a condition, disorder ordisease that is characterised by activation of (1) one or morecomponents of the necrosome; (2) death domain receptors; and/or (3)Toll-like receptors; and/or (4) players in ferroptotic/ferroptosissignalling, or where activation of any one of (1) to (3) and/or (4) islikely to play or plays a substantial role; and (ii) a method oftreating an individual with a need thereof, comprising administering apharmaceutically effective amount of a compound of the invention, inparticular those specified above with respect to any of formulas (I),(N-I), (O/S-I), (C-I), (II), (N-II), (O/S-II), (C-II), (III), (N-III),(O/S-III), (C-III), (IV), (N-IV), (O/S-IV), (C-IV), (V), (N-V), (O/S-V),and (C-V) (or a pharmaceutical composition comprising such compoundoptionally together with a pharmaceutically acceptable excipient), tothe individual. In one embodiment, the individual is suffering from, oris susceptible to or at risk of, one or more of the conditions,disorders or diseases disclosed herein. The condition, disorder ordisease may be selected from the group consisting of a neurodegenerativedisease of the central or peripheral nervous system, muscle wasting,muscular dystrophy, ischemia, compartment syndrome, gangrene, pressuresores, sepsis, degenerative arthritis, retinal necrosis, heart disease,liver, gastrointestinal or pancreatic disease, avascular necrosis,diabetes, sickle cell disease, alteration of blood vessels,cancer-chemo/radiation therapy-induced cell-death, intoxication, or isthe result of, arises from or is associated with any of the foregoing.In a further embodiment, the condition, disorder or disease is theresult of, arises from or is associated with a circumstance selectedfrom the group consisting of forms of infection of viruses, bacteria,fungi, or other microorganisms; a reduction in cell-proliferation, analteration in cell-differentiation or intracellular signalling; anundesirable inflammation; cell death of retinal neuronal cells, cardiacmuscle cells, or cells of the immune system, cell death associated withrenal failure; neonatal respiratory distress, asphyxia, incarceratedhernia, placental infarct, iron-load complications, endometriosis,congenital disease; head trauma/traumatic brain injury, liver injury;injuries from environmental radiation; burns; cold injuries; mechanicalinjuries, and decompression sickness. Moreover, the individual ispreferably a mammal and more preferably a human.

The compounds of the invention may be used in such therapeutic or otherapplications as described above for the following particularembodiments:

-   -   the treatment (including prophylactic treatment) of a condition,        disorder or disease that is characterised by sequelae and        associated pathophysiological responses, including but not        limited to immunological, damage-associated molecular pattern        molecules (DAMPs);    -   to improve cell and tissue regeneration, including in a        therapeutic or ex-vivo application;    -   the treatment (including prophylactic treatment) of a condition,        disorder or disease that is characterised by the involvement of        players in ferroptotic/ferroptosis signalling, such as GPx4, or        of xCT (SLC7A11) of the xc-amino acid transport system, or where        the contribution of the foregoing is likely to play or plays a        substantial role;    -   the treatment (including prophylactic treatment) of a condition,        disorder or disease: selected from the group consisting of:        cardiovascular (heart) disease, contrast-agent-induced toxicity,        and priapism, Lyme disease, Rocky Mountain spotted fever and        rabies;    -   the treatment (including prophylactic treatment) of a condition,        disorder or disease that is the result of, arises from or is        associated with: the side effects of medications, or of snake,        scorpion or spider bites;    -   to decrease and/or delay non-apoptotic cell death, including in        a therapeutic or ex-vivo application; and/or    -   to increase cellular resistance against cell-death stimuli,        including in a therapeutic or ex-vivo application.

The compounds of the invention (or the pharmaceutical compositioncomprising such compound) may be administered to the individual by anyroute, preferably by any route described above in section“Pharmaceutical compositions” for the administration of thepharmaceutical composition of the invention.

Synthesis and Intermediates

The compounds of the present invention can be prepared as describedbelow or prepared by methods analogous thereto, which are readily knownand available to one of ordinary skill in the art of organic synthesis.

Compounds disclosed herein may be prepared by the general syntheticsequence shown in Scheme 1, below.

For example, compounds 4 (i.e., compounds of the present invention) maybe synthesized in a one-step reaction from applicable derivatives ofdiamine 1, ketone 2 and isocyanide 3. The synthesis can be conducted asfollows. A mixture of 0.5 mmol of diamine 1 and 0.5 mmol of ketone 2 in0.5 mL methanol is stirred under nitrogen atmosphere at 40-45° C. for 3h. To this mixture, solutions of 0.5 mmol TMSCl in 0.5 mL acetonitrileand 0.5 mmol of isocyanide 3 in 0.5 mL methanol are added and theresulting mixture stirred at 50-60° C. for 4 h and then for 1 day at40-50° C., resulting in full conversion of starting materials(monitoring can be done by using LC-MS). The reaction mixture isevaporated under reduced pressure, treated with dry ethylacetate andkept in an ultrasonic bath until completion of precipitate formation.The reaction mixture is then centrifuged and the precipitate washedtwice with ethylacetate, acetonitrile and ether with centrifugation eachtime and finally dried under reduced pressure. Compounds 4 are obtainedas monohydrochloride salts, typically in pure form, and at yields of50-90%.

Compounds 4 which bear a functional group that may interfere with thereaction set forth in Scheme 1 can be prepared according to Scheme 1using a corresponding starting material (e.g., diamine 1, ketone 2and/or isocyanide 3 or a suitable synthon of any of the foregoing) whichis suitably protected at the functional group so that the correspondingprotected starting material no longer interferes with the reaction setforth in Scheme 1, followed by a subsequent deprotection step of theprotected precursor version of 4. For example, compounds 4 which areunsubstituted on a ring nitrogen atom of ring A (i.e., N—R⁹ being N—H;cf., e.g., compounds N-1 to N-89, N-111 to N-190 and N-199 to N-203 ofTable 1-N) can be prepared according to Scheme 1, generally inaccordance with the method described above using a ketone 2 which issuitably protected at the ring nitrogen atom(s) of ring A, followed by asubsequent deprotection step of the protected precursor version of 4.The skilled person knows suitable protecting groups (for example,N-protecting groups, such as the BOC protecting group), reagents andreaction conditions in order to covert a “free” functional group (e.g.,an amino group having at least one hydrogen bound to the nitrogen atom,such as —NH—) into a corresponding protected functional group (such as—N(PG)-, wherein PG is a protecting group), as well as reagents andreaction conditions in order to remove the protecting group (cf., e.g.,Protective Groups in Organic Synthesis (Theosora W. Greene & Peter G. M.Wuts; John Wiley & Sons Inc., 1999). In case of the BOC protectinggroup, the deprotection step may be performed as follows. A mixture of0.5 mmol of compound 4 (with —N(R⁹)— being —N(C(O)O-tBu)- prepared byusing the applicable —CO—O-tBu containing ketone 2) in 2 mLmethylenechloride and 1 mL TFA is stirred overnight at room temperatureand the reaction mixture evaporated to dryness under reduced pressure.The residue is dissolved in THF and treated with an excess of HCl indioxane (8M) and then with acetonitrile. The precipitate is collected bycentrifugation, washed with acetonitrile and then ethyl acetate,followed each time by centrifugation; and thereafter is dried underreduced pressure to yield deprotected compound 4, typically in pureforms and in yields of 85-90%. Alternatively, if, for example, astarting material (e.g., a specific diamine 1, ketone 2 and/orisocyanide 3) as such cannot be handled under the reaction conditionsutilized to prepare compounds 4 according to Scheme 1, a suitablesynthon of the specific diamine 1, ketone 2 and/or isocyanide 3 may beused instead. E.g., the skilled person knows that a synthon of a cyclicketon is its corresponding hemiacetal; for example, a synthon ofcyclopropanone is cyclopropanone ethyl hemiacetal (such as1-ethoxy-1-(trimethylsilyloxy) cyclopropane) which is much easier andsafer to handle than cyclopropanone and which easily reacts with amines(cf., e.g., Organic Syntheses, Coll. Vol. 7, p. 131 (1990); Vol. 63, p.147 (1985)).

Precursors 1, 2 and 3 (wherein R², R³, R⁴, R⁵, ring A, L, and G are asdefined above for the compounds of the invention) are obtained fromcommercial sources, or are synthesised by standard procedures. Inparticular, derivatives of isocyanide 3 may be obtained using theprocedures described by Hoefle and Lange (Organic Syntheses (1983)61:14).

Thus, in further aspects, the present invention relates to intermediates1, 2, and/or 3 which are useful in the preparation of a compound of thepresent invention as well as to a method of preparing a compound of thepresent invention comprising the step of reacting a diamine of formula1, a ketone of formula 2 and an isocyanide of formula 3. Preferably,such preparation or method is represented by scheme 1.

Regioisomers of compounds 4 (e.g., compounds N-135 to N-182 of Table1-N, compounds O/S-114 to O/S-161 and O/S-282 to O/S-329 of Table 1-O/S,and compounds C-155 to C-202 of Table 1-C) may be isolated bychromatography separation, for example HPLC separation, as will berecognised and practicable by the person of ordinary skill. Enantiomersof racemic mixtures of compounds 4 (e.g., compounds N-82 and N-83 ofTable 1-N, compounds O/S-82, O/S-83, O/S-248, and O/S-249 of Table1-O/S, and compounds C-82 and C-83 of Table 1-C) may be isolated byseparation using commercial services and/or products, e.g., those fromChiral Technologies Europe SAS (www.chiral.fr).

A person of ordinary skill will appreciate that other routes ofsynthesis or separation may be employed as well. In particular, otherroutes of synthesis may in fact be applied to certain embodiments of thecompounds disclosed herein. The person of ordinary skill is referred togeneral textbooks, such as March's Advanced Organic Chemistry (MichaelB. Smith & Jerry March, Wiley-Interscience, 2000), The Practice ofMedicinal Chemistry (Camile G. Wermuth, Academia Press, 2003) andProtective Groups in Organic Synthesis (Theosora W. Greene & Peter G. M.Wuts; John Wiley & Sons Inc, 1999).

EXAMPLES

A selection of compounds within the scope of, or for use within themethods of, the present invention is listed in Tables 1-N, 1-O/S, and1-C. The compounds in Tables 1-N, 1-O/S, and 1-C are synthesisedaccording to Example A, and the surprising cell-death inhibitoryactivities in cellular assays of non-apoptotic regulated cell-death ofsuch compounds are shown in Table 2, Table 3 and FIGS. 1(a), (b), and(c), FIGS. 2(a), (b), and (C), and FIGS. 3 and 4, respectively, asdetermined according to Examples B.1 to B.3, B.4, and B.5. The use ofsuch compounds in animal models of certain medical conditions, disordersand diseases is described in Examples C.1 to C.8, and procedures tofurther select and/or develop one or more of such compounds as drugs aredescribed in Example D.

Example A: Synthesis of Spiroquinoxaline Derivatives

Analytical Devices Used

Analytical LC/ESI-MS: Waters 2700 Autosampler. Waters 1525 MultisolventDelivery System. 5 μL sample loop. Column, Phenomenex Onyx MonolythicC18 50×2 mm, with stainless steel 2 μm prefilter. Eluent A, H₂O+0.1%HCOOH; eluent B, acetonitrile. Gradient, 5% B to 100% B within 3.80 min,then isocratic for 0.20 min, then back to 5% B within 0.07 min, thenisocratic for 0.23 min; flow, 0.6 ml/min and 1.2 ml/min.

Waters Micromass ZQ 4000 single quadrupol mass spectrometer withelectrospray source. MS method, MS4_15 minPM-80-800-35V;positive/negative ion mode scanning, m/z 80-800 in 0.5 s; capillaryvoltage, 3.50 kV; cone voltage, 50 V; multiplier voltage, 650 V; sourceblock and desolvation gas temperature, 120° C. and 300° C.,respectively. Waters 2487 Dual λ Absorbance Detector, set to 254 nm.Software, Waters Masslynx V 4.0.

Waters Micromass LCZ Platform 4000 single quadrupol mass spectrometerwith electrospray source. MS method, MS4_15 minPM-80-800-35V;positive/negative ion mode scanning, m/z 80-800 in 1 s; capillaryvoltage, 4.0 kV; cone voltage, 30 V; multiplier voltage, 900 V; sourceblock and desolvation gas temperature, 120° C. and 300° C.,respectively. Waters 996 Photodiode Array Detector, set 200 to 400 nm.Software, Waters Masslynx V4.0.

Values for [M+H]⁺ given in Table 3 are those found within thecorresponding LC/MS chromatogram for the respective compound. Thesevalues were all found within tolerable margins of +/−0.3 units comparedto calculated exact mass upon protonation of the compound.

Preparative thinlayer chromatography (preparative TLC): Merck PLCplates, silica gel 60 F₂₅₄, 0.5 mm, 1.0 mm or 2.0 mm. Eluents forpreparative TLC or column chromatography (CC) on silica gel were: (1)EluentN1: CH₂Cl₂/methanol; EluentN2: CH₂Cl₂/methanol/NEt₃ forspiroquinoxaline derivatives having an N-heterocycloalkylene as ring A;(2) EluentO1: CH₂Cl₂/ethyl acetate/methanol; EluentO2: CH₂Cl₂/methanol;EluentO3: petroleum ether/ethyl acetate for spiroquinoxaline derivativeshaving an O/S-heterocycloalkylene as ring A; or (3) EluentC1:CH₂Cl₂/ethyl acetate/methanol; EluentC2: CH₂Cl₂/methanol; EluentC3:petroleum ether/ethyl acetate; EluentC4: CH₂Cl₂/methanol/NEt₃ forspiroquinoxaline derivatives having a cycloalkylene as ring A. For eacheluent, the aforementioned solvents were used in different ratios,depending on the respective compound.

Preparative HPLC-MS: Waters 2767 Autosampler, Waters 600 MultisolventDelivery System with analytical pump heads (100 μL); Waters 600Controller; Waters 2525 Binary Gradient Modul with preparative pumpheads (500 μL). At-Column-Dilution: solvent1, acetonitrile:H₂O 70:30(v/v), solvent2, acetonitrile:methanol:dimethylformamide 80:15:5(v/v/v); flow rate, 5 mL/min. Autosampler 2767 with 10 mL syringe and 10mL Sample loop. Column 6-position valve Flom 401 with Waters X-TerraRP18, 5 μm, 19×150 mm with X-Terra RP18 guard cartridge 5 μm, 19×10 mm,used at flow rate 20 mL/min; Waters SunFire Prep OBD 5 μm, 30×50 mm withSunFire RP18 guard cartridge 5 μm, 19×10 mm, used at flow rate 25mL/min; Waters Atlantis Prep T3 OBD 5 μm, 30×50 mm with Atlantis guardcartridge, used at flow rate 50 mL/min; Waters X-Bridge Prep OBD 5 μm,19×150 mm with X-Bridge RP18 guard cartridge 5 μm, 19×10 mm used at flowrate 20 mL/min; Waters Atlantis Prep T3 OBD 5 μm, 19×50 mm with Atlantisguard cartridge, used at flow rate 25 mL/min and YMC-Actus HydrosphereC18 5 μm, 20×50 mm with Actus guard cartridge, used at flow rate 20mL/min. Eluent A, H₂O containing 0.1% (v/v) HCO₂H or H₂O containing 0.1%(v/v) NEt₃; eluent B, acetonitrile. Different linear gradients,individually adapted to sample. Injection volume, 9 mL, depending onsample. Make-up solvent, methanol-acetonitrile-H₂O—HCO₂H 80:15:4.95:0.05(v/v/v/v). Make-up pump, Waters Reagent Manager, flow rate 0.5 mL/min.Waters ZQ single quadrupole mass spectrometer with electrospray source.Positive or negative ion mode scanning m/z 105-950 in 1 s; capillary,3.6 kV; cone voltage, 45 V; multiplier voltage, 700 V; probe anddesolvation gas temperature, 120° C. and 250° C., respectively. WatersFraction Collector 2767 with mass or UV-triggered fraction collection.Waters 2487 Dual λ Absorbance Detector, set to 254 nm. Software, WatersMasslynx V 4.0 SP4.

¹H NMR spectra were recorded at room temperature on a BrukerSupraleitendes Fourier NMR Spektrometer, Avance™ 300 MHz. Chemicalshifts 6 were recorded in ppm. Multiplicity of a certain signal(singlet, doublet, triplet, quartet, multiplet) was recorded by therespective abbreviation (s, d, t, q, m respectively), with “s_(br.)”indicating a broad singlet, and “mC” a centered multiplet. The solventresidual signals were used as internal standards: δ(CDCl₃)=7.26,δ(d6-DMSO)=2.50, δ(CD₃OD)=3.31, δ(d6-acetone)=2.05.

General Methods for Synthesis and Workup

Compounds disclosed herein may be prepared by the synthetic sequenceaccording to Scheme 1 as set fourth above (cf. chapter “Synthesis andintermediates”, above).

(I) For example, compounds 4 may be formed in a one-step reaction fromapplicable derivatives of diamine 1, ketone 2 and isocyanide 3 asfollows. A mixture of 0.5 mmol of diamine 1 and 0.5 mmol of ketone 2 in0.5 mL methanol is stirred under nitrogen atmosphere at 40-45° C. for 3h. To this mixture, solutions of 0.5 mmol TMSCl in 0.5 mL acetonitrileand 0.5 mmol of isocyanide 3 in 0.5 mL methanol are added and theresulting mixture stirred at 50-60° C. for 4 h and then for 1 day at40-50° C., resulting in full conversion of starting materials(monitoring can be done by using LC-MS). The reaction mixture isevaporated under reduced pressure, treated with dry ethylacetate andkept in an ultrasonic bath until completion of precipitate formation.The reaction mixture is then centrifuged and the precipitate washedtwice with ethylacetate, acetonitrile and ether with centrifugation eachtime and finally dried under reduced pressure. Compounds 4 are obtainedas monohydrochloride salts, typically in pure form, and at yields of50-90%.

(I.1) A general method for the synthesis of compound 4, wherein ring Ais an N-heterocycloalkylene and R⁹ bound to a ring nitrogen atom is notH, is as follows. A mixture of 0.46 mmol of diamine 1 and 0.46 mmol ofketone 2 in 2.0 mL methanol was stirred at 50° C. for 4 hours. To thismixture, solutions of 0.46 mmol TMSCl in 0.50 mL acetonitrile and 0.46mmol of isocyanide 3 in 0.50 mL methanol were added and the resultingmixture was stirred at 50-60° C. for 4 hours and then at r.t. (roomtemperature, i.e., usually about 25° C.) overnight which resulted infull consumption of starting materials (LC-MS). Workup and purificationwas performed by one of the following procedures PN1a and PN1b.Procedure PN1a: The reaction mixture was diluted with 1N HCl and waterand then extracted twice with ethyl acetate. The combined organic layers(F1) contained no or only minor product (LC-MS) and were thus discarded.The aqueous layer was then basified with 1N NaOH and extracted severaltimes with CH₂Cl₂. The combined organic layers (F2) were dried overNa₂SO₄ and concentrated in vacuo. The residue was purified bypreparative HPLC and/or preparative TLC. Procedure PN1b: The reactionmixture was diluted with water, neutralized with saturated aqueousNaHCO₃ and then extracted several times with CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative HPLC and/or preparative TLC and/orwas transferred into to the corresponding HCl salt by dissolving indiethyl ether and/or CH₂Cl₂, adding 4N HCl in dioxane and filtering offthe resulting precipitate.

(I.2) A general method for the synthesis of compound 4, wherein ring Ais an N-heterocycloalkylene and R⁹ bound to a ring nitrogen atom is H,is as follows. A mixture of 0.46 mmol of diamine 1 and 0.46 mmol ofBoc-protected ketone 2 in 2.0 mL methanol was stirred at 50° C. for 4hours. To this mixture, solutions of 0.46 mmol TMSCl in 0.50 mLacetonitrile and 0.46 mmol of isocyanide 3 in 0.50 mL methanol wereadded and the resulting mixture was stirred at 50-60° C. for 4 hours andthen at r.t. overnight which resulted in full consumption of startingmaterials (LC-MS). Workup and purification was performed by one of theprocedures PN2a to PN2c described below, followed by the general WorkupPW below. Procedure PN2a: The reaction mixture was diluted with 2.0 mLethyl acetate and/or 2.0 mL CH₂Cl₂, then 1.0 mL HCl 4M in dioxane wasadded and the mixture was stirred at r.t. for 1-3 days. Procedure PN2b:The reaction mixture was diluted with water, neutralized with saturatedaqueous NaHCO₃ and extracted several times with CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative TLC and then dissolved in 2.0 mLethyl acetate. 1.0 mL HCl 4.0 M in dioxane was added and the mixture wasstirred at r.t. for 1-3 days. Procedure PN2c: The reaction mixture wasdiluted with water, neutralized with saturated aqueous NaHCO₃ andextracted several times with CH₂Cl₂. The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo. The residue was dissolvedin 2.0 mL ethyl acetate and/or 2.0 mL CH₂Cl₂ and/or 2.0 mL methanol. 1.0mL HCl 4.0 M in dioxane was added and the mixture was stirred at r.t.for 1-3 days. Workup PW: The reaction mixture was diluted with water andthen extracted twice with ethyl acetate. The combined organic layers(F1) contained no or only minor product (LC-MS) and were thus discarded.The aqueous layer was then basified with 1N NaOH and extracted severaltimes with CH₂Cl₂. The combined organic layers (F2) were dried overNa₂SO₄ and concentrated in vacuo. The residue was purified bypreparative HPLC and/or preparative TLC.

(I.3) A general method for the synthesis of compound 4, wherein ring Ais an O/S-heterocycloalkylene, is as follows. A mixture of 0.46 mmol ofdiamine 1 and 0.46 mmol of ketone 2 in 2.0 mL methanol was stirred at50° C. for 4 hours. To this mixture, solutions of 0.46 mmol TMSCl in0.50 mL acetonitrile and 0.46 mmol of isocyanide 3 in 0.50 mL methanolwere added and the resulting mixture was stirred at 50-60° C. for 4hours and then at r.t. overnight which resulted in full consumption ofstarting materials (LC-MS). Workup and purification was performed by oneof the following procedures POa to POd. Procedure POa: The reactionmixture was diluted with 1N HCl and water. The resulting precipitate wasfiltered off and washed with water. The filtrate contained no product(LC-MS) and was thus discarded. The crude product was taken up inCH₂Cl₂, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by preparative TLC. Procedure POb: The reactionmixture was diluted with 1N HCl and water and then extracted twice withethyl acetate. The combined organic layers (F1) contained no or onlyminor product (LC-MS) and were thus discarded. The aqueous layer wasthen basified with 1N NaOH and extracted several times with CH₂Cl₂. Thecombined organic layers (F2) were dried over Na₂SO₄ and concentrated invacuo. The residue was purified by preparative HPLC and/or preparativeTLC and/or recrystallization from ethanol and/or was transferred into tothe corresponding HCl salt by dissolving in diethyl ether and/or CH₂Cl₂,adding 4N HCl in dioxane and filtering off the resulting precipitate.Procedure POc: The reaction mixture was diluted with water (40 mL) andextracted several times with CH₂Cl₂. The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative HPLC and/or preparative TLC and/orrecrystallization from ethanol and/or was transferred into to thecorresponding HCl salt by dissolving in diethyl ether and/or CH₂Cl₂,adding 4N HCl in dioxane and filtering off the resulting precipitate.Procedure POd: The reaction mixture was diluted with water (40 mL),neutralized with sat. NaHCO₃ and extracted several times with CH₂Cl₂.The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by preparative HPLCand/or preparative TLC and/or recrystallization from ethanol and/or wastransferred into to the corresponding HCl salt by dissolving in diethylether and/or CH₂Cl₂, adding 4N HCl in dioxane and filtering off theresulting precipitate.

(I.4) A general method for the synthesis of compound 4, wherein ring Ais a C-heterocycloalkylene, is as follows. A mixture of 0.46 mmol ofdiamine 1 and 0.46 mmol of ketone 2 in 2.0 mL methanol was stirred at50° C. for 4 hours. To this mixture, solutions of 0.46 mmol TMSCl in0.50 mL acetonitrile and 0.46 mmol of isocyanide 3 in 0.50 mL methanolwere added and the resulting mixture was stirred at 50-60° C. for 4hours and then at r.t. overnight which resulted in full consumption ofstarting materials (LC-MS). Workup and purification was performed by oneof the procedures PCa to PCc. Procedure PCa: The reaction mixture wasevaporated. The residue was treated with ethyl acetate under sonication,the formed precipitate was filtered off. The solid was washed withacetone and then partitioned between saturated. aqueous NaHCO₃ andCH₂Cl₂, the organic phase was washed several times with water and thecombined aqueous phases were extracted several times with CH₂Cl₂. Thecombined organic phases were dried over Na₂SO₄ and evaporated. Theresidue was purified by preparative TLC and/or recrystallization fromethanol. Procedure PCb: The reaction mixture was diluted with 1N HCl andwater and then extracted twice with ethyl acetate. The combined organiclayers (F1) contained no or only minor product (LC-MS) and were thusdiscarded. The aqueous layer was then basified with 1N NaOH andextracted several times with CH₂Cl₂. The combined organic layers (F2)were dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by preparative HPLC and/or preparative TLC and/orrecrystallization from ethanol and/or was transferred into to thecorresponding HCl salt by dissolving in diethyl ether and/or CH₂Cl₂,adding 4N HCl in dioxane and filtering off the resulting precipitate.Procedure PCc: The reaction mixture was diluted with water (40 mL) andextracted several times with CH₂Cl₂. The combined organic layers werewashed with brine and dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative HPLC and/or preparative TLC and/orrecrystallization from ethanol and/or was transferred into to thecorresponding HCl salt by dissolving in diethyl ether and/or CH₂Cl₂,adding 4N HCl in dioxane and filtering off the resulting precipitate.

(I.5) A general method for the synthesis of compound 4 with a freeNH₂-group by deprotection of a BOC-protected compound 4 is as follows. Amixture of 0.46 mmol of diamine 1 and 0.46 mmol of Boc-protected ketone2 in 2.0 mL methanol was stirred at 50° C. for 4 hours. To this mixture,solutions of 0.46 mmol TMSCl in 0.50 mL acetonitrile and 0.46 mmol ofisocyanide 3 in 0.50 mL methanol were added and the resulting mixturewas stirred at 50-60° C. for 4 hours and then at r.t. overnight whichresulted in full consumption of starting materials (LC-MS). The reactionmixture was diluted with 1N HCl (5.0 mL) and water and extracted severaltimes with CH₂Cl₂. The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by preparative TLCand dissolved in 2.0 mL ethyl acetate. 1.0 mL HCl 4.0 M in dioxane wasadded and the mixture was stirred at room temperature for 1 day. Thereaction mixture was diluted with water and extracted twice with ethylacetate. The combined organic layers (F1) contained no product and werethus discarded. The aqueous layer was basified with 1N NaOH andextracted several times with CH₂Cl₂. The combined organic layers (F2)were dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by preparative TLC.

Examples B: Cellular Activity Assays

The in-vitro cellular activity of compounds disclosed herein wasdemonstrated by one or more assays including those described in moredetail below.

Example B.1

Inhibition of BSO-Induced Non-Apoptotic Cell Death by CompoundsDisclosed Herein

As shown in Table 2, the present inventors observed the surprisingfinding that compounds disclosed herein are (presumed) able to penetratecell membranes and showed activity as inhibitors of non-apoptotic celldeath induced in cells of the human neuroblastoma cell line SH-SY5Ygrown in-vitro.

L-Buthionine sulfoximine (BSO) is a well-known glutathione (GSH)depletory, which inhibits gamma-glutamyl-cysteine-synthetase, the enzymecatalyzing the rate-limiting step in GSH biosynthesis. The humanneuroblastoma cell line SH-SY5Y is sensitive to BSO-inducedintracellular glutathione depletion, which causes high levels ofreactive oxygen species (ROS) and cellular stress mimicking cellularconditions following ischemia (cf., e.g., Yamada et al., Neurochem. Int.59:1003-9 (2011)).

Compounds disclosed herein were evaluated for their ability to promotecell survival upon administration of a lethal dose of BSO tocell-culture medium. Briefly, SH-SY5Y cells (ATCC® CRL-2266™) werepropagated in DMEM supplemented with 10% FBS/1% Penicillin-Streptomycin,and then seeded onto 96-well plates at a concentration of 750 cells/wellin 100 μL of media, to which BSO (Sigma Aldrich) was added (to a finalconcentration of 50 μM) together with increasing concentrations of thecompound to be tested, and the plates incubated at 37° C./5% CO₂ for 72hours. Compound dilutions (0.5 pM to 100 μM) were prepared from 10 mMstocks dissolved in DMSO and diluted in media. Cells treated with BSOalone were used as negative control and alpha-Tocopherol (Sigma Aldrich)was used as positive control. Compound concentrations were tested intriplicate. After incubation, cell survival was detected using thelive/dead cell assay AquaBluer™ (MultiTarget Pharmaceuticals) andquantified using a fluorescence plate reader (excitation filter: 530-560nm/emission filter: 590 nm) (SpectraMax M4; Molecular Devices).Fluorescence data so obtained was normalised to the percentage ofsurviving cells and IC₅₀ values calculated using the GraphPad Prism(GraphPad Software, Inc) software package. Such IC₅₀ values obtained forcertain compounds disclosed herein are shown in Table 2 and Table 3.

TABLE 2 SH-SY5Y/BSO Ht22/GLU (Example B.1) (Example B.2) Compound No.IC₅₀ (nM) IC₅₀ (nM) N-1 6.51 10.3 N-2 2.81 ~10 N-10 ~5 10-50 O/S-3 ~100~100 O/S-6 68.28 218.4 C-12 468 297.6 C-91 9.33 ~50 C-205 46.67 ~100

TABLE 3 MW Therapeutic (theor./meas. SH-SY5Y/BSO Ht22/GLU Pfa1/TAM TC₅₀Window Cmpd. No. [M + H]⁺) IC₅₀ [μM] [μM] IC₅₀ [μM] [μM] (approx.. fold)N-1 340.86/340.88 <0.02 <0.2 <0.05 10-20 >500 N-2 340.86/340.88 <0.02<0.2 <0.02  5-10 >500 N-10 320.43/NT <0.02 <0.05 <0.1  5-10 >100 C-12319.44/NT <0.5 <0.5 <0.5  50-100 >100 C-91 353.89/NT <0.02 <0.2 <0.210-20 >100 O/S-6 325.38/NT <0.5 <0.5 <1  50-100 >200 O/S-3 341.84/341.90<0.5 <0.1 <0.5 20-50 >50 C-205 353.89/353.99 <0.1 <0.5 <0.2 20-50 >200O/S-337 307.17/307.99 <0.5 <5 <5  50-100 >20 C-214 319.21/320.04 <0.5 <1<0.5 10-20 >20 O/S-338 323.15/323.96 <0.5 <5 <1  50-100 >100 C-215305.19/306.05 <0.2 <1 <1 20-50 >50 N-204 320.20/320.97 <0.05 <0.5 <0.520-50 >50 O/S-339 375.09/375.86 <0.02 <0.2 <0.05 20-50 >1000 O/S-1341.13/341.91 <0.5 <1 <1  50-100 >100 C-1 339.86/339.94 <0.5 <1 <0.520-50 >100 O/S-2 341.13/341.89 <0.2 <1 <0.5 20-50 >50 N-205375.30/374.84 <0.02 <0.05 <0.01 1-2 >100 O/S-340 335.20/336.02 <0.2 <0.5<0.5 20-50 >100 O/S-168 357.11/357.88 <0.1 <0.5 <0.2 20-50 >200 N-99382.16/382.95 <0.2 <1 <1  50-100 >100 C-216 353.89/353.99 <0.05 <0.5<0.1 10-20 >100 C-217 373.11/373.91 <0.05 <0.2 <0.05 20-50 >500 O/S-167357.11/357.89 <1 <0.5 20-50 >100 C-218 333.22/334.01 <0.1 <0.120-50 >200 N-206 306.18/306.97 <0.5 <0.2 20-50 >100 C-219 291.17/291.97<5 <2 20-50 >20 C-5 323.18/324.02 <5 <0.5 20-50 >50 O/S-5 325.16/326.02<5 <2  50-100 >50 N-5 324.18/324.96 <0.05 <0.1  5-10 >200 O/S-11321.18/322.02 <5 <2  50-100 >50 C-2 339.15/339.93 <0.1 <0.5 <0.110-20 >100 N-207 408.07/408.77 <0.05 <0.01 0.5-1   >500 N-115408.07/408.77 <0.05 <0.01 0.2-0.5 >200 C-23 373.18/373.98 <0.5 <0.0510-20 >100 C-3 339.15/339.95 <0.5 <0.2 20-50 >200 N-208 408.07/408.77<0.05 <0.01 0.5-1   >500 N-3 340.15/340.89 <0.05 <0.05 <0.01  5-10 >5000N-209 354.16/354.92 <0.5 <0.1  5-10 >100 N-90 354.16/354.92 <0.05 <0.2<0.02 10-20 >500 N-210 334.22/334.99 <0.05 <0.05 <0.01 2-5 >1000 C-11319.20/320.06 <1 <0.5 10-20 >20 N-111 368.18/368.92 <0.01 <0.011-2 >1000 O/S-23 375.16/375.97 <1 <0.5 20-50 >100 O/S-169 357.11/357.88<1 <1 20-50 >50 C-220 353.89/354.01 <0.5 <0.2 10-20 >50 C-268387.13/387.93 <0.5 <0.1 10-20 >100 C-47 335.20/336.04 <1 <0.5 20-50 >50C-221 333.22/334.07 <1 <1  5-10 >10 O/S-341 343.15/343.95 <2 <2 50-100 >50 C-222 341.17/342.01 <1 <0.2 20-50 >200 C-223 363.45/364.03<0.5 <1 <0.2 20-50 >200 O/S-94 409.05/409.83 <0.05 <0.5 <0.05 10-20 >200C-224 363.45/350.07 <1 <0.5 20-50 >50 C-79 353.89/354.00 <0.5 <0.52-5 >10 O/S-342 389.11/389.89 <0.1 <0.5 <0.05 20-50 >500 N-211374.11/374.85 <0.05 <0.01 1-2 >1000 N-212 320.20/320.97 <1 <1 10-20 >10C-225 333.22/334.03 <0.5 <0.5 10-20 >20 N-213 354.16/354.92 <0.2 <0.1 5-10 >100 N-214 368.18/368.90 <0.05 <0.01 1-2 >1000 O/S-14337.18/338.02 <5 <5  50-100 >20 O/S-343 335.20/336.03 <5 <2 20-50 >20C-226 319.20/320.04 <2 <1 10-20 >10 O/S-344 335.20/336.04 <2 <120-50 >50 C-227 397.16/397.94 <0.5 <1 <0.05 20-50 >1000 O/S-345375.09/375.84 <0.1 <0.5 <0.1 20-50 >500 C-228 373.11/373.92 <0.05 <0.5<0.05 20-50 >500 N-215 388.19/388.93 <0.05 <0.05  5-10 >500 C-229395.24/396.01 <1 <0.2 2-5 >10 O/S-346 343.15/343.94 <1 <0.5  50-100 >200N-56 374.11/374.85 <0.05 <0.01 1-2 >1000 C-269 361.25/362.04 <0.5 <0.2 5-10 >20 O/S-347 321.18/321.98 <5 <5  50-100 >20 C-230 373.11/373.88<0.5 <0.1 20-50 >200 N-216 432.29/433.03 <0.5 <0.5 10-20 >20 N-217334.22/334.98 <0.05 <0.05 <0.1 20-50 >200 N-79 354.16/354.92 <0.05 <0.12-5 >50 N-218 320.20/320.99 <0.5 <0.5 20-50 >100 N-219 398.15/398.86<0.5 <1 <1 20-50 >50 O/S-348 321.18/321.99 <5 <5  50-100 >20 O/S-79355.15/355.97 <1 <1 20-50 >50 N-220 396.23/396.99 <0.05 <0.02 <0.052-5 >200 C-231 341.17/342.00 <1 <0.5 20-50 >50 O/S-349 391.07/391.87<0.5 <0.2 20-50 >200 N-221 342.17/342.95 <0.2 <0.2 20-50 >200 C-232347.24/348.06 <1 <2 20-50 >20 N-222 348.23/349.00 <0.05 <0.2 20-50 >200C-233 347.24/348.04 <1 <1 20-50 >20 O/S-350 363.23/363.98 <0.5 <0.520-50 >100 O/S-351 359.13/359.94 <1 <1  50-100 >100 O/S-352397.22/398.00 <1 <1 20-50 >50 N-14 336.20/336.98 <0.2 <0.5 20-50 >100N-23 374.17/374.92 <0.02 <0.05 <0.05 20-50 >1000 C-61 357.14/357.95 <0.5<0.2 20-50 >100 N-61 358.14/358.92 <0.05 <0.05 <0.05 20-50 >1000 N-223342.17/342.95 <0.05 <0.05 <0.05 20-50 >1000 N-224 388.12/388.83 <0.05<0.01 1-2 >1000 C-137 375.13/375.91 <0.2 <0.2 <0.2 10-20 >100 C-234421.09/421.89 <0.5 <0.5 20-50 >100 C-235 387.13/387.96 <0.5 <0.210-20 >50 C-236 333.22/334.06 <0.5 <0.5 10-20 >50 C-237 401.14/401.95<0.5 <0.5 10-20 >50 O/S-61 359.12/359.89 <1 <1 20-50 >50 N-225348.23/348.97 <1 <0.05 1-2 >50 N-226 320.20/321.01 <0.1 <0.1 10-20 >200C-238 341.17/342.02 <0.2 <0.5 20-50 >100 O/S-353 349.22/350.00 <2 <0.520-50 >50 N-227 362.25/363.01 <0.01 <0.01 0.5-1   >200 O/S-354375.09/375.85 <0.5 <0.5 20-50 >200 N-228 334.22/335.01 <0.05 <0.12-5 >50 N-229 356.18/356.92 <0.1 <0.1  5-10 >50 N-230 388.12/388.86<0.01 <0.01 <0.01 0.5-1   >200 C-239 347.24/348.01 <0.2 <0.2 10-20 >50N-231 342.17/342.95 <0.1 <0.05 <0.05 10-20 >200 N-232 402.14/402.86<0.01 <0.01 1-2 >1000 N-233 348.23/348.98 <0.1 <0.2 10-20 >50 C-240409.09/409.85 <0.2 <0.5  5-10 >20 O/S-355 343.15/343.98 <2 <2 50-100 >20 C-241 361.25/362.04 <0.2 <0.5  5-10 >20 C-242 355.19/356.02<1 <1 10-20 >10 C-243 421.09/421.85 <1 <0.5 10-20 >20 O/S-356351.18/352.00 <2 <2 20-50 >20 N-234 418.31/419.03 <0.1 <0.1  5-10 >50O/S-357 351.18/351.99 <0.5 <0.5 10-20 >20 C-244 319.20/320.07 <1 <110-20 >10 O/S-358 349.22/349.99 <2 <2 10-20 >5 O/S-359 359.13/359.96<5 >5  50-100 >5 N-235 348.23/348.97 <0.05 <0.05 1-2 >20 O/S-189391.13/391.88 <5 <5  50-100 >20 O/S-360 423.06/423.78 <2 <2 NT NTO/S-361 or 341.13/341.90 <0.5 <0.5 20-50 >200 O/S-362 O/S-361 and341.13/341.94 <0.5 <0.5 20-50 >100 O/S-362 C-245 and 333.22/334.07 <0.1<0.05  5-10 >100 C-246 C-247 or C- 373.11/373.94 <0.5 <0.5 10-20 >20 248C-247 or C- 373.11/373.88 <2 <2 10-20 >5 248 O/S-363 355.14/355.93 <2 <5<2 10-20 >5 N-236 388.12/388.83 <0.05 <0.1 2-5 >50 C-249 362.21/363.02<1 <5 <5  50-100 >20 C-250 or C- 407.07/407.79 <0.2 <1 <1 10-20 >10 251C-250 or C- 407.07/407.86 <0.5 <2 <2  5-10 >5 251 C-252 319.20/320.05<0.2 <1 <1 10-20 >10 O/S-364 or 375.09/375.87 <0.1 <1 <1 10-20 >10O/S-365 C-253 333.22/334.06 <0.1 <1 <1 10-20 >10 N-237 or N-320.20/321.01 <0.02 <0.05 <0.1  5-10 >100 238 N-239 354.16/354.92 <0.05<0.2 <1  5-10 >10 C-111 396.17/396.98 <0.5 <1 <1 10-20 >10 N-240320.20/321.01 <0.1 <0.5 <0.5 10-20 >50 N-241 or N- 374.11/374.85 <0.05<0.05 <0.05 0.2-0.5 >10 242 N-241 or N- 374.11/374.85 <0.02 <0.05 <0.11-2 >10 242 N-243 or N- 374.17/374.92 <0.01 <0.05 <0.1 1-2 >20 244 C-254373.18/373.98 <0.05 <0.5 <0.5  5-10 >20 N-245 or N- 340.15/340.94 <0.01<0.05 <0.1 2-5 >20 246 C-255 381.20/381.96 <0.05 <0.2 <0.2  5-10 >50C-206 367.18/367.97 <0.05 <0.5 <0.5  5-10 >10 O/S-366 387.14/387.92<0.05 <0.1 <0.1 20-50 >200 C-256 385.16/385.86 <0.05 <0.2 <0.120-50 >200 C-257 320.20/321.01 <0.1 <0.5 <0.2 2-5 >20 N-247 or N-334.22/334.99 <0.05 <0.05 <0.1 2-5 >50 248 N-249 and 320.20/321.01 <0.05<0.1 <0.1 2-5 >50 N-250 N-251 402.20/402.94 <0.01 <0.05 <0.1 0.5-1   >10N-252 and 374.17/374.96 <0.05 <0.1 <0.1 1-2 >10 N-253 N-254 and340.15/340.94 <0.01 <0.05 <0.05 1-2 >20 N-255 C-258 339.15/339.91 <0.05<0.5 <0.2 10-20 >50 C-259 373.18/373.95 <0.1 <0.5 <0.5  5-10 >20 N-256334.22/334.99 <0.05 <0.5 <0.5 10-20 >20 N-257 352.21/352.98 <0.02 <0.1<0.1 1-2 >20 O/S-367 337.16/337.96 <0.2 <0.5 <1 20-50 >20 O/S-368337.16/338.01 <2 <2 <5 20-50 >10 N-258 442.03/442.69 <0.02 <0.05 <0.10.1-0.2 >2 C-260 455.11/455.98 <0.05 <0.5 <0.2  5-10 >50 C-261387.19/388.03 <0.05 <0.5 <0.5 10-20 >20 C-262 415.16/415.95 <0.1 <0.5<0.5 10-20 >20 C-263 319.20/320.03 <0.05 <0.5 <0.5 10-20 >20 N-117376.13/376.86 <0.01 <0.05 <0.05 1-2 >20 N-259 376.13/376.86 <0.01 <0.05<0.05 1-2 >50 C-264 441.10/441.93 <0.05 <0.5 <0.5 10-20 >20 O/S-369351.18/351.94 <0.05 <0.2 <0.1 10-20 >100 C-265 409.09/409.80 <0.05 <0.5<0.5 10-20 >50 N-260 442.09/442.77 <0.02 <0.05 <0.02 0.5-1   >20 N-185354.16/354.92 <0.05 <0.5 <0.2 1-2 >5 O/S-370 389.10/389.92 <1 <5 <2 50-100 >20 N-261 474.37/475.06 <0.02 <0.2 <0.1 2-5 >20 N-262362.25/363.01 <0.02 <0.05 <0.05 0.5-1   >10 C-266 355.19/356.01 <0.1<0.5 <0.5 10-20 >20 C-267 401.14/401.87 <0.1 <0.5 <0.2 10-20 >50 MW:molecular weight (theoretical/measured as [M + H]⁺ using HPLC/MS), seeExample A for details; SY5Y/BSO: see Example B.1 for details; Ht22/GLU:see Example B.2 for details; Pfa1/TAM see Example B4 for details; TC₅₀and Therapeutic Window: see Example B.5 for details; NT: not tested

Example B.2

Inhibition of Glutamate-Induced Non-Apoptotic Cell Death by Compounds ofthe Present Invention

As also shown in Table 2, the present inventors observed the surprisingfinding that compounds disclosed herein showed activity as inhibitors ofanother model of non-apoptotic cell death induced in cells of the mousehippocampal cell line (Ht22) grown in-vitro.

Glutamate toxicity is conferred on cells from the mouse hippocampal cellline (Ht22) by inhibition of the cysteine/glutamate antiporter, Systemxc-, leading to impaired cysteine uptake and subsequent GSH depletion.This model is frequently used for mimicking glutathione depletionfollowing oxidative stress in stroke, brain trauma and otherneurodegenerative diseases and cellular conditions following ischemia(for example: van Leyen et al, J. Neurochem. 92:824-30 (2005)).

Compounds disclosed herein were evaluated for their ability to promotecell survival upon administration of a lethal dose of glutamate (GLU) tothe cell-culture medium.

Briefly, Ht22 cells (ATCC) were propagated DMEM supplemented with 10%FBS/1% Penicillin-Streptomycin, and then seeded onto 96-well plates at aconcentration of 2,000 cells/well in 100 μL of MEDIA, simultaneouslywith glutamate (Sigma Aldrich) to a final concentration of 5 mM,together with increasing concentrations of the compound to be tested(0.5 pM to 100 μM), and the plates incubated at 37° C./5% CO₂ for 72hours. Compound dilutions were prepared from 10 mM stocks dissolved inDMSO and diluted in media. Cells treated with glutamate alone were usedas negative control and alpha-tocopherol (Sigma Aldrich) was used aspositive control. Compound concentrations were tested in triplicate.After incubation, cell survival was detected and quantified as describedin Example B.1. IC₅₀ values in such assay obtained for certain compoundsdisclosed herein are shown in Table 2 and Table 3.

Example B.3

Specificity for Inhibition of Non-Apoptotic Cell Death by Compounds ofthe Present Invention.

As shown in FIG. 1, the present inventors observed the surprisingfinding that compounds disclosed herein that showed activity asinhibitors of non-apoptotic cell death (as described above), did notappear to inhibit cell-death in an assays for classical apoptosis (forexample: Alikhani et al., J. Cell Physiol. 201:341-8 (2004)).

Without being bound by theory, apoptosis (e.g., as assays in ExampleB.3) is believed to occur under or as a result of normal physiologicalconditions or events in a highly programmed manner as part of normaltissue homeostasis and cell turnover; while, conversely, non-apoptoticregulated cell death is thought to be triggered by abnormalphysiological conditions or events such as external damaging stimuliand/or oxidative stress. Compounds that inhibit non-apoptotic regulatedcell-death but do not appear to inhibit apoptotic cell-death may havepreferred utility in the methods and applications of the presentinvention, as they may not interfere with the individual's innatecell-death mechanism and regulation, but preferentially only that causedby abnormal physiological conditions or events such as external damagingstimuli and/or oxidative stress.

Briefly, SH-SY5Y cells were propagated and seeded in 96-well plates,together with the compound to be tested (1 μM), generally as describedin Example B.1, except they were seeded at 1,000 cell/well and insteadof BSO, TNF-alpha (Invitrogen) was added to a final concentration of 10ng/mL to induce apoptosis. The apoptosis and pan-caspase inhibitorZ-VAD-fmk (Enzo Life Science; final concentration 50 μM) and thenecroptosis inhibitor Necrostatin-1 (Nec-1; Enzo Life Science; finalconcentration 5 μM) were used for comparison. Control wells wereestablished with vehicle only (DMSO), with and without treatment withTNF-alpha to induce apoptosis. Cells were incubated, and cell survivalwas detected and quantified as described in Example B.1. Percentage cellsurvival after TNF-alpha-induced apoptosis for certain compoundsdisclosed herein are shown in FIG. 1. Surprisingly, those compoundstested appear to show more specificity than Nec-1 at known activeconcentrations.

Example B.4

Inhibition of Non-Apoptotic Cell-Death by Compounds Disclosed HereinUsing a Recombinant Cell Line

To combat high intracellular ROS levels, mammalian cells have evolved anintricate network of ROS scavenging in cells, in which the thioredoxinand glutathione (GSH) dependent systems prevail. Within the GSH system,glutathione peroxidase 4 (GPx4) is the most central player, asdemonstrated by targeted knockout of the GPx4 gene in mice. GPx4knockout causes early embryonic death at the same stage as mice lackingendogenous GSH synthesis, demonstrating that GPx4 is a key ROScontrolling enzyme. A conditional GPx4 knockout mouse model, whichallows experimental manipulation of endogenous ROS levels to mimicdegenerative diseases (Seiler, A., et al, 2008; Cell Metab 8:237) wasused to show that oxidative stress causes cell death by a specificsignaling pathway entailing lipid peroxide generation andapoptosis-inducing-factor mediated cell death (Mannes et al, 2011; FASEBdoi: 10.1096/fj.10-177147). Knockout of GPx4 in neurons causes massiveneurodegeneration in cortical, cerebellar and hippocampal neuronsunderscoring the high relevance of ROS-induced cell death signaling inthe brain. Briefly, immortalised fibroblasts from these mice were madeto contain tamoxifen-inducible CreERT2, which catalyzes the functionalablation of both copies of GPx4 and resulting in a complete knockout ofGPx4, a massive ROS burst, and cell death in cell culture. These cells(Pfa1 cells) were used to characterize compounds of the presentinvention, whereby tamoxifen (TAM) was given on day 0 along with thecompound under test, and 72 hours later cell survival was evaluatedusing AlamarBlue. Using a compound concentration range from 0.5picomolar to 100 micromolar and GraphPad Prism, the IC₅₀ of each testedcompound was estimated. Such IC₅₀ values obtained for certain compoundsdisclosed herein are shown in Table 3.

Example B.5

Cellular Toxicity of Compounds of the Invention

An estimate of the toxicity for compounds of the invention was obtainedby using the same assay as described in Example B.4, but without theaddition of TAM. Compounds were so tested over a concentration rangefrom 100 nanomolar to 100 micromolar and the resulting TC₅₀ valueestimated using GraphPad Prism. Such TC₅₀ values obtained for certaincompounds disclosed herein, together with an approximate therapeuticwindow (estimated by dividing each TC₅₀ by the corresponding IC₅₀determined from example B.4) are shown in Table 3.

Examples C: Activity in Animal Models of Conditions, Disorders andDiseases

The in-vivo activity of compounds disclosed herein is demonstrated byone or more animal models including those described in more detailbelow.

Example C.1

Utility of Compounds Disclosed Herein for the Treatment ofLiver-Ischemic-Reperfusion Injury

Compounds disclosed herein are found to have surprising utility in thetreatment of ischemia-reperfusion injury (IRI) of the liver, using anin-vivo murine model of such condition/disorder/disease.

Compounds of the invention that reduce IRI damage in the liver can beproposed as drug-candidates and have utility as medicines for limitingorgan trauma upon transplantation and other diseases or conditionscaused by ischemia-reperfusion and such utility can be tested in an invivo model, for example, as described by Abe et al. (Free Radic. Biol.Med. 46: 1-7 (2009)).

Briefly, to test such utility of compounds disclosed herein, ischemia isinduced in the liver of 6-8 week old C57BL/6 mice (Charles River) bymidline laparotomy whereby the blood supply to the left and median lobesof the liver is interrupted via atraumatic clipping for 90 min, followedby reperfusion for a period of 24 h. After reperfusion, but prior tofinal abdominal closure, animals are treated with a single i.p. dose ofthe compound to be tested (10 mg/Kg), or with vehicle (DMSO) as negativecontrol. Markers to be investigated for IRI of liver include liverparameters from serum (ALT/GPT, AST/GOT, Bilirubin, Urea),histopathological analysis and rtPCR of inflammatory and non-apoptoticcell death markers (such as TNF-alpha and INF-gamma). FIGS. 2(a) and (b)show a significant reduction of the serum markers for liver cell damage,GPT and GOT, respectively (compared to vehicle control), upon treatmentwith a compound of the invention (N-2) of mice following IRI liverdamage. The “Sham” bar represents the data from control animals thatwere treated to the same protocol but without atraumatic clipping. FIG.2(c) shows a photograph representing a visual comparison between vehicleand compound-treated livers of mice from this study.

Example C.2

Utility of Compounds Disclosed Herein for the Treatment ofKidney-Ischemic-Reperfusion Injury

Compounds disclosed herein are investigated for their utility in thetreatment of ischemia-reperfusion injury (IRI) of the kidney, using anin-vivo murine model of such condition/disorder/disease.

Compounds of the invention that reduce IRI damage in the kidney can beproposed as drug-candidates and have utility as medicines for limitingorgan trauma upon transplantation and other diseases or conditionscaused by ischemia-reperfusion, and such utility can be tested in an invivo model, for example, as described by Wu et al. (J. Clin. Invest.117:2847-59 (2007)) and Linkermann et al. (Kidney Int. 81: 751-761(2012)).

Briefly, to test such utility of compounds disclosed herein, ischemia isinduced in the kidney of 6-8 week old C57BL/6 mice by interruption ofthe blood supply to the kidney via reversible clipping of the Arteriarenalis for 30 min, followed by reperfusion for a period of 24 h. Miceare treated with compound (or vehicle control) generally as described inExample C.1 at 1 hour prior to and four hours after abdominal closureand once daily over a period of 14 days. Markers to be investigated forIRI of kidney include reduction of creatinine levels in the serum alongwith histopathological analysis. FIG. 3 shows an improvement of survivalof mice suffering kidney-ischemic reperfusion injury (compared tovehicle control) after treatment with a compound of the invention (N-2)at a dose of both 1 and 10 mg/kg.

Example C.3

Utility of Compounds Disclosed Herein for the Treatment of Paracetamol(APAP) Intoxication

Compounds disclosed herein are investigated for their utility in thetreatment of APAP intoxication, using an in-vivo murine model of suchcondition/disorder/disease.

Compounds of the invention that inhibit non-apoptotic regulatedcell-death can be proposed as drug-candidates and have utility asmedicines for limiting the effects of APA intoxication, and such utilitycan be tested in an in vivo model, for example, as described byPatterson et al. (Chem. Res. Toxicol. 2013, “Article ASAP Webpublication”, date 22 May 2013).

Briefly, to test such utility of compounds disclosed herein, groups of6-8 week-old male C57BL/6 mice are given an i.p. injection of APAP (400mg/kg) in saline, and at the same time or at a given time thereafter,compounds to be tested are administered (1 mg/Kg or 10 mg/Kg) by i.p.injection, or vehicle (DMSO) as control. Mice are sacrificed by CO₂asphyxiation 6 h after the APAP dose, and to assess liver damage, liversare removed and washed in phosphate buffered saline, and portions ofliver tissue are fixed in 10% buffered formalin or flash frozen at −80°C. The extent of non-apoptotic cell death is scored by haematoxylin andeosin staining. The extent of APAP-induced liver injury is determined bymeasuring aspartate aminotransferase (AST) and alanine aminotransferase(ALT) catalytic activities in serum. Reduced GSH levels in liver andliver mitochondria extracts are measured using a glutathione assay kit.

Example C.4

Utility of Compounds Disclosed Herein for the Treatment of CisplatinIntoxication

Compounds disclosed herein are investigated for their utility in thetreatment of cisplatin intoxication, using an in-vivo murine model ofsuch condition/disorder/disease.

Compounds of the invention that inhibit non-apoptotic regulatedcell-death can be proposed as drug-candidates and have utility asmedicines for limiting the effects of cisplatin intoxication, and suchutility can be tested in an in vivo model, for example, as described byTristao et al. (Ren. Fail. 34:373-7 (2012)).

Briefly, to test such utility of compounds disclosed herein, one daybefore single cisplatin treatment (25 mg/Kg i.p dissolved in 40% PEG),vehicle (DMSO) as control or compounds to be tested are administered (1mg/Kg or 10 mg/Kg), e.g. injected i.p., in 6-8 week-old C57BL/6 malemice. Compound (or vehicle control) treatment is continued daily duringan observation period of four to five days. Three days after cisplatintreatment, liver, spleen, and kidney samples are dissected forhistopathological analysis. Blood samples are collected to determineblood urea nitrogen and plasma creatinine levels.

Example C.5

Utility of Compounds Disclosed Herein for the Treatment of TraumaticBrain Injury

Compounds disclosed herein are investigated for their utility in thetreatment of traumatic brain injury, using an in-vivo murine model ofsuch condition/disorder/disease.

Non-apoptotic regulated cell death plays a major role in thepathogenesis of traumatic brain injury (TBI), and the utility ofcompounds of the invention as a medicine for suchcondition/disorder/disease can be investigated using an in-vivo murinemodel for example as described by You et al. (J. Cereb. Blood FlowMetab. 28:1564-73 (2008)), or Rauen et al. (J. Neurotrauma 30:1442-8(2013)).

Briefly, to test such utility of compounds disclosed herein, maleC57BL/6 mice are anesthetised prior to the induction of trauma. Corebody temperature is maintained at 37° C. using a feedback-controlledheating pad connected to a rectal probe. To induce trauma, a craniotomyis prepared over the right parietal cortex. Controlled cortical impact(CCI) is delivered perpendicular to the surface of the brain with acustom-made CCI applicator for mice using the following parameters: 8m/s velocity, 3 mm diameter, 1 mm brain displacement and 150 msduration. Following CCI, the skull is closed by affixing the removedbone flap using veterinary-grade tissue glue (Vetbond, 3M, St. Paul,Minn.). Compounds are administered at 1 mg/Kg or 10 mg/Kg (dissolved in40% PEG) 15 minutes after TBI induction and 40% PEG is included asvehicle control. The animals are recovered from anesthesia in anincubator heated to 33° C. Animals are sacrificed and the brain isremoved 24 h after CCI and immediately frozen on crushed dry ice andstored at −80° C. Coronal sections (10 μm thick) are cut from rostral tocaudal using a cryostat (CryoStar HM 560; Microm, Walldorf, Germany),and 1 in every 50 sections is prepared for further analysis. Thesections are stained with cresyl violet for quantifying the area ofcontused brain, and contusion volume is calculated and the effect of thecompounds tested observed following analysis of such data. FIG. 4 showsa trend of a (non-significant) positive effect of treatment with acompound of the invention (N-2), reducing the contusion volume in thebrains of mice following TBI.

Example C.6

Utility of Compounds Disclosed Herein for the Treatment of RheumatoidArthritis (RA)

Compounds disclosed herein are investigated for their utility in thetreatment of RA, using an in-vivo murine model of suchcondition/disorder/disease.

The collagen-induced arthritis (CIA) mouse model is the most commonlystudied autoimmune model of rheumatoid arthritis, for example asdescribed by Brand et al. (Nat. Protoc. 2:1269-75 (2007)), and can beused to study the utility of compounds of the invention to treat RA.

Briefly, to test such utility of compounds disclosed herein, RA isinduced in this model by immunization with an emulsion of completeFreund's adjuvant and type II collagen as described in Brand et al.(2007). Compounds are administered daily by i.p. injections starting atday one. 40% PEG is used as vehicle control. Mice are monitored dailyand disease progression is assessed using a scoring system.

Example C.7

Utility of Compounds Disclosed Herein for the Treatment of MultipleSclerosis (MS)

Compounds disclosed herein are investigated for their utility in thetreatment of MS, using an in-vivo murine model of suchcondition/disorder/disease.

Experimental autoimmune encephalomyelitis (EAE) is the most commonlyused experimental model for the human inflammatory demyelinatingdisease, multiple sclerosis (MS), for example as described by Racke(Curr. Protoc. Neurosci. 9: unit 9.7 (2001)), and can be used to studythe utility of compounds of the invention to treat MS.

Briefly, to test such utility of compounds disclosed herein, EAE isinduced as described in Racke (2001). Compounds are administered dailyby i.p. injections starting at day one. 40% PEG is used as vehiclecontrol. Mice are monitored daily and disease progression is assessedusing a scoring system.

Example C.8

Utility of Compounds Disclosed Herein for the Treatment ofLipopolysaccharide (LPS)-Induced Endotoxic Shock

Compounds disclosed herein are investigated for their utility in thetreatment of LPS-induced endotoxic shock, using an in-vivo murine modelof such condition/disorder/disease.

Compounds of the invention that inhibit non-apoptotic regulatedcell-death can be proposed as drug-candidates and have utility asmedicines for limiting the effects of LPS-induced endotoxic shock, andthis utility can be investigated using an in-vivo murine model forexample as described by Duprez et al. (Immunity 35:908-18 (2011)).

Briefly, to test such utility of compounds disclosed herein, endotoxicshock is induced by i.p. injection of LPS at a dose of 20 mg/kg of bodyweight in 6-8 week-old male C57BL/6 mice. Compounds to be tested areadministered daily (1 mg/Kg or 10 mg/Kg) by i.p. injection, or vehicle(DMSO) as control, for a subsequent observation period of 4 days.Survival of mice is monitored by inspection twice daily for 5 days.

Example D: Selection and Development of Drug Candidates

In order to select the most appropriate compound to enter furtherexperiments and to assess its suitability for use in atherapeutic/pharmaceutical composition for the treatment of one or moreconditions, disorders and/or diseases, additional data are collected.Such data can include the in vitro inhibition of non-apoptoticcell-death, in particular inhibition of necroptosis or ferroptosis, asmeasured by IC₅₀, or from applicable in-vivo animal models ofconditions, disorders and/or diseases. Furthermore, such experiments mayalso include the elucidation and/or determination of the target ormechanism of action of the subject compound or the target profile of thesubject compound, and other characteristics of the subject compound,such as the binding affinity of the compound to the target(s) or thebinding site of the compound on the target(s) and pharmacokineticproperties. Such experiments may also include molecular modelling of thedrug-target interaction and the identification of metabolites formedafter administration.

The compound that shows the most appropriate results for IC₅₀ forinhibition of non-apoptotic cell-death inhibition and/or in-vivoanimal-model data, and/or other features, including absorption,distribution, metabolism, and excretion (ADME), pharmacokinetic andpharmacodynamic properties, may be chosen to enter further experiments.Such experiments may include, for example, therapeutic profiling andtoxicology in animals, phase I clinical trials in humans and otherclinical trails.

The invention claimed is:
 1. A method for treating a condition, disorderor disease in a subject in need thereof, the method comprisingadministering to the subject a compound selected from the groupconsisting of a spiroquinoxaline derivative having the general formula(I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemicmixtures, diastereomers, enantiomers, tautomers, isotopically labeledforms, prodrugs, and combinations thereof, wherein E is —N(R⁶)—; L isselected from the group consisting of C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene,C₂₋₁₀ alkynylene, 1,1-(CH₂)_(a)-cyclopropylene-(CH₂)_(b)—, wherein eachof a and b is independently selected from an integer between 0 and 3,and —(CH₂)_(m)—[Y—(CH₂)_(n)]_(o)—, wherein m is an integer between 1 and6, n is an integer between 0 and 3, o is an integer between 1 and 3,wherein if n is 0 then o is 1; Y is independently selected from O, S,and —N(R⁷)—; and each of the C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, C₂₋₁₀alkynylene, 1,1-cyclopropylene, —(CH₂)_(m)—, and —(CH₂)_(n)— groups isoptionally substituted with one or more independently selected R³⁰; G isphenyl, optionally substituted with 1, 2, 3, 4 or 5 independentlyselected R⁸; ring A is a monocyclic 4- to 10-memberedN-heterocycloalkylene, a monocyclic 4- to 10-memberedO/S-heterocycloalkylene, or a monocyclic 3- to 10-memberedcycloalkylene, wherein each of the N-heterocycloalkylene,O/S-heterocycloalkylene, and cycloalkylene groups is optionallysubstituted with one or more independently selected R⁹; R¹ is H; R², R³,R⁴, and R⁵ are independently selected from the group consisting of —H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,halogen, —CN, azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —N(R¹¹)(OR¹¹),—S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹, —OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹,—NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹,—XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups isoptionally substituted with one or more independently selected R³⁰; orR² and R³ may join together with the atoms to which they are attached toform a ring which is optionally substituted with one or moreindependently selected R³⁰; R³ and R⁴ may join together with the atomsto which they are attached to form a ring which is optionallysubstituted with one or more independently selected R³⁰; and/or R⁴ andR⁵ may join together with the atoms to which they are attached to form aring which is optionally substituted with one or more independentlyselected R³⁰; R⁶ is H; R⁷ is selected from the group consisting of —H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,—OR¹¹, and —NHR²⁰, wherein each of the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionallysubstituted with one or more independently selected R³⁰; R⁸ is, in eachcase, selected from the group consisting of alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO₂,—OR¹¹, —N(R¹²)(R¹³), —N(R¹¹)(OR¹¹), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹,—OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹,—C(═X)XR¹¹, —XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groupsis optionally substituted with one or more independently selected R³⁰;R⁹ is, when substituting a hydrogen atom bound to a ring carbon atom,independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN,azido, —NO₂, —OR¹¹, —N(R¹²)(R¹³), —S(O)₀₋₂R¹¹, —S(O)₁₋₂OR¹¹,—OS(O)₁₋₂R¹¹, —OS(O)₁₋₂OR¹¹, —S(O)₁₋₂N(R¹²)(R¹³), —OS(O)₁₋₂N(R¹²)(R¹³),—N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹, —NR¹¹S(O)₁₂N(R¹²)(R¹³), —C(═X)R¹¹,—C(═X)XR¹¹, —XC(═X)R¹¹, and —XC(═X)XR¹¹, wherein each of the alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groupsis optionally substituted with one or more independently selected R³⁰,and/or any two R⁹ which are bound to the same carbon atom of ring A mayjoin together to form ═X; or R⁹ is, when substituting a hydrogen atombound to a ring nitrogen atom, independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, —OR¹¹, —N(R¹²)(R¹³), —S(O)₁₋₂R¹¹, —S(O)₁₋₂OR¹¹,—S(O)₁₋₂N(R¹²)(R¹³), —N(R¹¹)S(O)₁₋₂R¹¹, —NR¹¹S(O)₁₋₂OR¹¹,—NR¹¹S(O)₁₋₂N(R¹²)(R¹³), —C(═X)R¹¹, —C(═X)XR¹¹, —N(R¹⁴)C(═X)R¹¹, and—N(R¹⁴)C(═X)XR¹¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups is optionallysubstituted with one or more independently selected R³⁰; or R⁹ is, whenbound to a ring sulfur atom of ring A, independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, —OR¹¹, and ═O, wherein each of the alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groupsis optionally substituted with one or more independently selected R³⁰; Xis independently selected from O, S, and N(R¹⁴); R¹¹ is, in each case,selected from the group consisting of —H, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclylgroups is optionally substituted with one or more independently selectedR³⁰; R¹² and R¹³ are, in each case, independently selected from thegroup consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl, or R¹² and R¹³ may join together with thenitrogen atom to which they are attached to form the group —N═CR¹⁵R¹⁶,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more independently selected R³⁰; R¹⁴ is independently selected fromthe group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocyclyl, and —OR¹¹, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups isoptionally substituted with one or more independently selected R³⁰; R¹⁵and R¹⁶ are independently selected from the group consisting of —H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and—NH_(y)R²⁰ _(2-y), or R¹⁵ and R¹⁶ may join together with the atom towhich they are attached to form a ring which is optionally substitutedwith one or more independently selected R³⁰, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groupsis optionally substituted with one or more independently selected R³⁰; yis an integer from 0 to 2; R²⁰ is selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl groups is optionally substituted with oneor more independently selected R³⁰; and R³⁰ is a 1^(st) levelsubstituent and is, in each case, independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, halogen, —CN, azido, —NO₂, —OR⁷¹, —N(R⁷²)(R⁷³),—S(O)₀₋₂R⁷¹, —S(O)₁₋₂OR⁷¹, —OS(O)₁₋₂R⁷¹, —OS(O)₁₋₂OR⁷¹,—S(O)₁₋₂N(R⁷²)(R⁷³), —OS(O)₁₋₂N(R⁷²)(R⁷³), —N(R⁷¹)S(O)₁₋₂R⁷¹,—NR⁷¹S(O)₁₋₂OR⁷¹, —NR⁷¹S(O)₁₋₂N(R⁷²)(R⁷³), —C(═X¹)R⁷¹, —C(═X¹)X¹R⁷¹,—X¹C(═X¹)R⁷¹, and —X¹C(═X¹)X¹R⁷¹, and/or any two R³⁰ which are bound tothe same carbon atom of a cycloalkyl or heterocyclyl group may jointogether to form ═X¹, wherein each of the alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, and heterocyclyl groups being a 1^(st) levelsubstituent is optionally substituted by one or more 2^(nd) levelsubstituents, wherein said 2^(nd) level substituent is, in each case,independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3- to 14-membered aryl, 3- to 14-memberedheteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-memberedheterocyclyl, halogen, —CF₃, —CN, azido, —NO₂, —OR⁸¹, —N(R⁸²)(R⁸³),—S(O)₀₋₂R⁸¹, —S(O)₁₋₂OR⁸¹, —OS(O)₁₋₂R⁸¹, —OS(O)₁₋₂OR⁸¹,—S(O)₁₋₂N(R⁸²)(R⁸³), —OS(O)₁₋₂N(R⁸²)(R⁸³), —N(R⁸¹)S(O)₁₋₂R⁸¹,—NR⁸¹S(O)₁₋₂OR⁸¹, —NR⁸¹S(O)₁₋₂N(R⁸²)(R⁸³), —C(═X²)R⁸¹, —C(═X²)X²R⁸¹,—X²C(═X²)R⁸¹, and —X²C(═X²)X²R⁸¹, and/or any two 2^(nd) levelsubstituents which are bound to the same carbon atom of a cycloalkyl orheterocyclyl group being a 1^(st) level substituent may join together toform ═X², wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-memberedcycloalkyl, 3- to 14-membered heterocyclyl groups being a 2^(nd) levelsubstituent is optionally substituted with one or more 3^(rd) levelsubstituents, wherein said 3^(rd) level substituent is, in each case,independently selected from the group consisting of C₁₋₃ alkyl, halogen,—CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃ alkyl), —OCF₃, —S(C₁₋₃ alkyl),—NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl),—S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z), —C(═O)OH, —C(═O)O(C₁₋₃ alkyl),—C(═O)NH_(2-z)(C₁₋₃ alkyl)_(z), —NHC(═O)(C₁₋₃ alkyl),—NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and —N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃alkyl)_(z), wherein z is 0, 1, or 2 and C₁₋₃ alkyl is methyl, ethyl,propyl or isopropyl, and/or any two 3^(rd) level substituents which arebound to the same carbon atom of a 3- to 14-membered cycloalkyl orheterocyclyl group being a 2^(nd) level substituent may join together toform ═O, ═S, ═NH, or ═N(C₁₋₃ alkyl); wherein R⁷¹, R⁷², and R⁷³ areindependently selected from the group consisting of —H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-memberedaryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl,wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3- to7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-memberedheteroaryl, and 3- to 7-membered heterocyclyl groups is optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂, —OH, —O(C₁₋₃alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z),—C(═O)(C₁₋₃ alkyl), —C(═O)OH, —C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z), —NHC(═O)(C₁₋₃ alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and—N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2and C₁₋₃ alkyl is methyl, ethyl, propyl or isopropyl; R⁸¹, R⁸², and R⁸³are independently selected from the group consisting of —H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3- to 6-membered cycloalkyl, 5- or6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-memberedheterocyclyl, wherein each of the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups isoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁₋₃ alkyl, halogen, —CF₃, —CN, azido, —NO₂,—OH, —O(C₁₋₃ alkyl), —OCF₃, ═O, —S(C₁₋₃ alkyl), —NH₂, —NH(C₁₋₃ alkyl),—N(C₁₋₃ alkyl)₂, —NHS(O)₂(C₁₋₃ alkyl), —S(O)₂NH_(2-z)(C₁₋₃ alkyl)_(z),—C(═O)(C₁₋₃ alkyl), —C(═O)OH, —C(═O)O(C₁₋₃ alkyl), —C(═O)NH_(2-z)(C₁₋₃alkyl)_(z), —NHC(═O)(C₁₋₃ alkyl), —NHC(═NH)NH_(z-2)(C₁₋₃ alkyl)_(z), and—N(C₁₋₃ alkyl)C(═NH)NH_(2-z)(C₁₋₃ alkyl)_(z), wherein z is 0, 1, or 2and C₁₋₃ alkyl is methyl, ethyl, propyl or isopropyl; and X¹ and X² areindependently selected from O, S, and N(R⁸⁴), wherein R⁸⁴ is —H or C₁₋₃alkyl, wherein the condition, disorder or disease is: (ii) a condition,disorder or disease where oxidative stress caused by glutathionedepletion plays a role; (iv) a condition, disorder or disease selectedfrom the group consisting of a neurodegenerative disease of the centralor peripheral nervous system, muscle wasting, muscular dystrophy,ischemia, compartment syndrome, gangrene, pressure sores, sepsis,degenerative arthritis, retinal necrosis, heart disease, liver,gastrointestinal or pancreatic disease, avascular necrosis, diabetes,sickle cell disease, alteration of blood vessels, cancer-chemo/radiationtherapy-induced cell-death and intoxication, paracetamol (APAP)intoxication, cisplatin intoxication, traumatic brain injury, rheumatoidarthritis, multiple sclerosis, lipopolysaccharide (LPS)-inducedendotoxic shock, ischemia reperfusion injury, Alzheimer's disease,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS), dementia or is the result of, arises from or is associated withany of the foregoing; and/or (v) a condition, disorder or disease whichis the result of, arises from or is associated with a circumstanceselected from the group consisting of forms of infection of viruses, orfungi; a reduction in cell-proliferation, an alteration incell-differentiation or intracellular signalling; an undesirableinflammation; cell death of retinal neuronal cells, cardiac musclecells, or cells of the immune system or cell death associated with renalfailure; neonatal respiratory distress, asphyxia, incarcerated hernia,placental infarct, iron-load complications, endometriosis, congenitaldisease; head trauma/traumatic brain injury, liver injury; injuries fromenvironmental radiation; burns; cold injuries; mechanical injuries, anddecompression sickness.
 2. The method of claim 1, wherein ring A is amonocyclic 4- to 10-membered N-heterocycloalkylene.
 3. The method ofclaim 1, wherein when R² to R⁵ are each H, L is —CH₂—, and (i) G isunsubstituted phenyl, then ring A is not

wherein R⁹ is —S(O)₂N(CH₃)₂, (cyclopropyl)sulfonyl, or(3-pyridinyl)sulfonyl, or R⁹ is —C(O)Z, wherein Z is methyl, tert-butyl,methoxymethyl, 2-methoxyethyl, —CH₂NHC(O)CH₃, 2-methoxyethylamino,morpholin-4-ylmethyl, 2-furanylmethylamino,(2-methyl-1H-imidazol-1-yl)methyl, 2-furanyl, 3-furanyl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1-ethyl-1H-pyrazol-3-yl, or1-ethyl-1H-pyrazol-5-yl; (ii) G is unsubstituted phenyl, then ring A isnot

wherein R⁹ is (1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl or —C(O)Z,wherein Z is 2-methoxyethylamino, methoxycarbonylmethylamino,(2-trifluoromethylphenyl)amino, 5-chloro-1H-indol-2-yl,4,5,6,7-tetrahydro-1H-indazol-3-yl, or 3-(2-thienyl)-1H-pyrazol-5-yl;(iii) G is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-methoxyphenyl, or 4-methoxyphenyl, then ring A is not

(iv) G is 3-methoxyphenyl, then ring A is not

wherein R⁹ is (3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl; (v) G is4-fluorophenyl, then ring A is not

wherein R⁹ is —C(O)Z, wherein Z is 6-methoxy-1H-indol-2-yl or3,4-dimethoxyphenyl; or (vi) G is 4-chlorophenyl, then ring A is not

wherein R⁹ is —C(O)Z, wherein Z is1-methyl-2-(2-methyl-1H-imidazol-1-yl)ethyl.
 4. The method of claim 1,wherein ring A is saturated.
 5. The method of claim 1, wherein ring Acontains 1 ring nitrogen atom and is 4- to 8-membered or contains 2 or 3ring nitrogen atoms and is 5- to 8-membered, preferably ring A is 5-, 6-or 7-membered, more preferably 6- or 7-membered.
 6. The method claim 1,wherein ring A is selected from the group consisting of piperidinylene,azepanylene (e.g., homopiperidinylene), azetidinylene, pyrrolidinylene,azocanylene, pyrazolidinylene, hexahydropyridazinylene,hexahydropyrimidinylene, diazepanylene (e.g., homopiperazinylene),diazocanylene, triazepanylene, and triazocanylene, each of which isoptionally substituted with one or more independently selected R⁹. 7.The method of claim 1, wherein ring A is a monocyclic 4- to 10-memberedO/S-heterocycloalkylene.
 8. The method of claim 1, wherein when ring Ais

R² and R⁵ are both H, L is —CH₂—, and (i) R³ and R⁴ are both H, then Gis not 3-methylphenyl, 3-methoxyphenyl, 4-chlorophenyl, or4-fluorophenyl; or (ii) R³ and R⁴ are both methyl, then G is not4-fluorophenyl.
 9. The method of claim 1, wherein ring A is saturated.10. The method of claim 1, wherein ring A contains 1 ring oxygen orsulfur atom and is 4- to 8-membered or contains 2 ring heteroatomsselected from oxygen and sulfur and is 5- to 8-membered, preferably ringA is 5-, 6- or 7-membered, more preferably 6- or 7-membered.
 11. Themethod of claim 1, wherein ring A is selected from the group consistingof di- and tetrahydropyranylene, di- and tetrahydrothiopyranylene,oxepanylene, thiepanylene, oxetanylene, thietanylene, di- andtetrahydrofuranylene, di- and tetrahydrothienylene, oxocanylene,thiocanylene, dithiolanylene, oxathiolanylene, dioxanylene,dithianylene, oxathianylene, dioxepanylene, dithiepanylene,oxathiepanylene, dioxocanylene, dithiocanylene, and oxathiocanylene,each of which is optionally substituted with one or more independentlyselected R⁹.
 12. The method of claim 1, wherein ring A is a monocyclic3- to 10-membered cycloalkylene.
 13. The method of claim 1, wherein whenR² and R⁵ are both H, L is —CH₂—, and (i) R³ and R⁴ are both H, and ringA is

then G is not unsubstituted phenyl, 4-methylphenyl, 3-methoxyphenyl, or4-methoxyphenyl; (ii) R³ and R⁴ are both H, and ring A is

then G is not 4-methylphenyl, 4-fluorophenyl, 3,5-difluorophenyl, or3-methoxyphenyl; (iii) R³ and R⁴ are both H, and ring A is

then G is not unsubstituted phenyl, 3-methylphenyl, 4-fluorophenyl,2-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl,3,5-difluorophenyl, or 4-trifluoromethylphenyl; (iv) R³ and R⁴ are bothH, and ring A is

then G is not 3-methoxyphenyl; (v) R³ and R⁴ are both H, and ring A is

then G is not unsubstituted phenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,3,5-difluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, or4-trifluoromethylphenyl; (vi) R³ and R⁴ are both methyl, and ring A is

then G is not 3-fluorophenyl or 3,5-difluorophenyl; (vii) R³ and R⁴ areboth methyl, and ring A is

then G is not 3-fluorophenyl or 3-methoxyphenyl; or (viii) R³ and R⁴ areboth methyl, and ring A is

then G is not unsubstituted phenyl, 2-methylphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, or 3-methoxyphenyl.
 14. The method ofclaim 1, wherein ring A is saturated.
 15. The method of claim 1, whereinring A is 3- to 8-membered, preferably 4-, 5-, 6- or 7-membered, morepreferably 6- or 7-membered.
 16. The method of claim 1, wherein ring Ais selected from the group consisting of cyclohexylene, cycloheptylene,cyclopropylene, cyclobutylene, cyclopentylene, cyclooctylene,cyclohexenylene, cycloheptenylene, cyclopentenylene, andcyclooctenylene, each of which is optionally substituted with one ormore independently selected R⁹.
 17. The method of claim 1, wherein thecondition, disorder or disease is selected from the group consisting of:paracetamol (APAP) intoxication, cisplatin intoxication, traumatic braininjury, rheumatoid arthritis, multiple sclerosis, lipopolysaccharide(LPS)-induced endotoxic shock, ischemia reperfusion injury, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), and dementia.